Compounds that interact with the RAS superfamily for the treatment of cancer, inflammatory diseases, rasopathy, and fibrotic diseases

Abstract

Compounds that interact with the RAS superfamily for the treatment of cancer, inflammatory diseases, rasopathy, and fibrotic diseases are provided. [Solution] Provided herein are compositions and methods for treating cancer, inflammatory diseases, rasopathy, and fibrotic diseases caused by aberrant Ras signaling involving members of the Ras superfamily of proteins, Ras, Rac, Rho, and Cdc42, through binding of compounds to the GTP-binding domains of these molecules. Also provided herein are novel cell-free assays for identifying small molecules that bind to the GTP-binding domains and compete with GTP binding to, for example, wild-type KRas, KRas G12D mutant, KRas G12C mutant, KRas Q61H mutant, KRas G12D / Q61H double mutant, KRas G12C / Q61H double mutant, Rac1, and RhoA proteins.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 523,114, filed June 21, 2017, which is incorporated herein by reference in its entirety.

[0002] Provided herein are compositions and methods for treating cancer, inflammatory diseases, rasopathy, and fibrotic diseases resulting from aberrant Ras signaling involving the Ras, Rac, Rho, and Cdc42 members of the Ras superfamily of proteins through binding of compounds to the GTP-binding domains of these molecules. [Background technology]

[0003] Cancer Pathobiology Cancer is primarily characterized by an increase in the number of abnormal cells derived from a given normal tissue, the invasion of adjacent tissues by these abnormal cells, or the lymphatic or blood-borne spread of malignant cells to regional lymph nodes and distant sites. Clinical data and molecular biological studies indicate that cancer is a multistep process beginning with small preneoplastic changes, which, under certain conditions, can progress to neoplasia. Neoplastic lesions can evolve clonally and develop increasing capacities for invasion, growth, metastasis, and heterogeneity, especially under conditions in which neoplastic cells escape the host's immune surveillance. (Roitt, I., Brostoff, J., and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993))

[0004] The various stages of tumor development can generally be described as follows:

[0005] a) Tumor development begins when cells within a normal population maintain genetic mutations that amplify their propensity to proliferate.

[0006] b) Although such genetically altered cells and their progeny continue to appear normal, they proliferate excessively, leading to a condition called hyperplasia. Altered cells may also secrete signaling factors or other molecules that cause changes in their local cellular and extracellular environment, including, but not limited to, immune system responses to them. Such environmental effects may in turn affect the survival, proliferation, and further mutations of the altered cells. After some time (months or years), a small fraction of these altered cells may sustain additional mutations, with subsequent loss of control over cell growth and further potential effects on their environment.

[0007] c) The progeny of these cells not only proliferate excessively but also appear abnormal in shape and orientation. At this point, the tissue is said to exhibit a condition called dysplasia. After some time, one or more additional mutations may further alter the behavior of the cells and their influence on their environment.

[0008] d) The affected, genetically altered cells become much more abnormal in growth and appearance. If the tumor mass does not invade through the boundaries between tissues, it is called an in situ tumor. This tumor can remain confined indefinitely, although some cells may acquire more mutations.

[0009] e) Malignant or invasive tumors occur when genetic changes allow the tumor mass to begin invading underlying tissues, releasing cells into the blood or lymph. The rogue cells can then introduce new tumor loci (metastases) throughout the body.

[0010] Metastasis represents the end product of a multistep cell biological process called the invasion-metastasis cascade, which involves the dissemination of cancer cells to anatomically distant organ sites and their subsequent adaptation to different tissue microenvironments. Each of these events is preceded by the acquisition of genetic and / or epigenetic alterations within tumor cells and the coexistence of non-neoplastic stromal cells, which together endow the initial metastatic cells with the traits necessary to generate macroscopic metastases. (Volastyan, S., et al., Cell, 2011, vol. 147, 275-292)

[0011] A vast array of cancers affect various tissues throughout the body and are well documented in the medical literature. Over 85% of human cancers are solid tumors, including carcinomas, sarcomas, and lymphomas. The various types of solid tumors are named for the type of cells that form them. Examples include cancer of the lung, colon, rectum, pancreas, prostate, breast, brain, and intestine. Other human tumors originate from cells involved in the formation of immune cells and other blood cells, including leukemia and myeloma.

[0012] The incidence of cancer continues to rise as the general population ages, as new cancers develop, and as the susceptible population grows. Therefore, there is a great demand for new methods and compositions that can be used to treat subjects with cancer.

[0013] How to Treat Cancer Current cancer therapies may include surgery, chemotherapy, hormonal therapy, biological therapy, targeted therapy, immunotherapy, and / or radiation therapy to eradicate neoplastic cells in patients (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV; and Baudino TA "Targeted Cancer Therapy: The Next Generation of Cancer Treatment", Curr Drug Discov Technol. 2015;12(1):3-20).

[0014] Such therapies may be used independently or in combination, and the choice of therapy will depend on the history and nature of the cancer, the condition of the patient, and, if applicable, the expected efficacy and adverse effects of the therapeutic agents and methods being considered.

[0015] With regard to chemotherapy, there are a variety of chemotherapeutic agents and delivery methods for such agents available for the treatment of various cancers. Most first-generation chemotherapeutic agents are not tumor-specific, have broad systemic effects, are toxic, and can cause serious and often dangerous side effects, including severe nausea, myelosuppression, and immunosuppression.

[0016] Furthermore, even when a combination of chemotherapy agents is administered, many tumor cells are or become resistant to the chemotherapy agents. In fact, cells that are resistant to a particular chemotherapy agent used in a treatment protocol often prove to be resistant to other drugs, even if those agents act by mechanisms different from those of the drugs used in the particular treatment. This phenomenon is called multidrug resistance. Due to drug resistance, many cancers are refractory to standard chemotherapy treatment protocols.

[0017] Therefore, there is a significant need for alternative compounds, compositions and methods for treating, preventing and managing cancer.

[0018] Furthermore, while surgical resection and adjuvant therapy can cure well-defined primary tumors, metastatic disease is largely incurable due to its systemic nature and the resistance of disseminated tumor cells to existing therapeutic agents, explaining why over 90% of cancer deaths are attributable to metastases rather than the primary tumors from which these malignancies arise.

[0019] Pathobiology of Inflammatory Diseases Inflammation is a complex, protective biological response of living tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, involving immune cells, vasculature, and molecular mediators. The function of inflammation is to eliminate the initial cause of cellular damage, remove damaged necrotic cells and tissue from the original injury and inflammatory process, and initiate tissue repair. (Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE; Nielsen; Andersen; Girardin (February 2007) Clin. Exp. Immunol. 147)

[0020] Inflammation is classified as either acute or chronic. Acute inflammation is the body's initial response to a harmful stimulus and is accompanied by increased movement of plasma and leukocytes (particularly granulocytes) from the blood to the injured tissue. A series of biochemical events propagates and matures the inflammatory response, involving the local vasculature, the immune system, and various cells within the injured tissue.

[0021] Long-term inflammation, known as chronic inflammation, is characterized by the simultaneous destruction and healing of tissue from the inflammatory process. It results in progressive changes in cell types present at the site of inflammation, such as mononuclear cells, and increased systemic concentrations of cytokines such as TNF-α, IL-6, and CRP. (Petersen, AM; Pedersen, BK (2005). J Appl Physiol. 98(4):1154-1162)

[0022] Many proteins are involved in inflammation, any of which are susceptible to genetic mutations that can impair or otherwise dysregulate their normal function and expression.

[0023] Methods for treating inflammatory diseases Both small molecules and biologics are used to treat inflammatory diseases, however most treatments are primarily palliative.

[0024] There remains a clear unmet medical need to find treatments that can mechanistically reduce chronic inflammatory diseases.

[0025] Pathobiology of fibrotic diseases Fibrosis, the accumulation of extracellular matrix molecules that constitute scar tissue, is a common consequence of tissue injury. Pulmonary fibrosis, renal fibrosis, and liver cirrhosis are some of the common fibrotic diseases that collectively represent a large unmet medical need. (Friedman SL, Sheppard D, Duffield JS, Violette S. Sci Transl Med Jan9;5(167)

[0026] The mechanisms of fibrosis include inflammatory and other pathways and generally involve reorganization of the actin cytoskeleton of affected cells, including epithelial cells, fibroblasts, endothelial cells, and macrophages.

[0027] Actin filament assembly and actomyosin contraction are directed by the Rho-associated coiled-coil forming protein kinase (ROCK) family of serine / threonine kinases (ROCK1 and ROCK2), and therefore Rho has been linked to fibril formation.

[0028] Tissue fibrosis is the leading cause of morbidity and mortality. 45% of deaths in the United States are attributable to fibrotic disorders. (Wynn TA. "Fibrotic Disease and the TH1 / TH2 Paradigm." Nat Rev Immunol 2004 Aug:4(8):583-594.) Treatment is generally palliative.

[0029] Idiopathic pulmonary fibrosis (IPF), characterized by progressive lung scarring, short median survival, and limited treatment options, is thought to result from repeated environmental insults to the lung epithelium, creating a critical need for new pharmacological therapies.

[0030] Targeted Therapies for Cancer, Inflammation, and Fibrotic Diseases Targeted therapies are a cornerstone of what is sometimes called precision medicine, a form of medicine that uses information about an individual's genes and proteins to prevent, diagnose, and treat disease. Such therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," or similar names. The process of discovering them is often referred to as "rational drug design."

[0031] The series of actions between molecules within a cell that leads to a given endpoint or cellular function is called a molecular pathway.

[0032] Molecularly targeted drugs interact with a specific target molecule, or a set of structurally related target molecules, within a pathway; thus, modulating the endpoint effect of that pathway, such as a disease-related process; and therefore, providing a therapeutic benefit.

[0033] Molecularly targeted agents can be small molecules or biologics, usually antibodies, which can be useful alone or in combination with other therapeutic agents and methods.

[0034] Because they target a specific molecule or set of related molecules and are usually designed to minimize their interactions with other molecules, targeted therapies may have fewer harmful side effects.

[0035] Targeted anticancer drugs broadly prevent the growth and spread of cancer by interacting with a specific molecule or set of structurally related molecules (collectively "molecular targets") that are involved in the growth, progression, lack of suppression or elimination, or spread of cancer. Such molecular targets may include, for example, proteins or genes involved in one or more cellular functions, including, but not limited to, signal transduction, gene expression regulation, apoptosis induction or suppression, angiogenesis inhibition, or immune system modulation.

[0036] In some cases, developing targeted cancer therapeutics involves identifying genes or proteins that are present in cancer cells but not in normal cells, or that are enriched or more highly stimulated in cancer cells, particularly if they are known to be involved in the cancer process, and then discovering agents that interact with those targets and are associated with the desired therapeutic effect.

[0037] Targeted cancer therapies generally differ from standard cancer chemotherapy in several ways: a. Targeted therapies are intentionally selected or designed to interact with their target(s), while many standard chemotherapeutics were identified because they are generally known to kill cells. b. Targeted therapies are intended to act on specific molecular targets associated with cancer, whereas most standard chemotherapeutics act on all rapidly dividing normal cells and cancer cells. However, they can also have known or sometimes unknown interactions with other molecules, so-called non-targeted effects. c. Most targeted therapies are cytostatic (i.e., they prevent tumor cell growth), while standard chemotherapeutic agents are usually cytotoxic (i.e., they kill tumor cells). However, some targeted therapies, such as antibody-drug conjugates, are cytotoxic.

[0038] Targeted therapy monoclonal antibodies (mAbs) and targeted small molecules are being used as treatments for inflammatory diseases (Kotsovilis S, Andreakos E., Methods Mol Biol. 2014;1060:37-59), either as monotherapy or in combination with other conventional treatment modalities, especially when the disease being treated is refractory to therapy using conventional techniques alone.

[0039] Several treatments for fibrotic disorders, such as idiopathic pulmonary fibrosis, liver fibrosis, and systemic sclerosis, target inflammatory pathways.

[0040] Ras GTPase family The Ras superfamily of proteins are small GTPases with substantial amino acid sequence homology that act as signal transducers between cell surface receptors and several intracellular signaling cascades. These molecules are involved in regulating essential cellular functions such as cell survival, proliferation, motility, and cytoskeletal organization (see Karnoub et al., Nat. Rev. Mol. Cell Biol., 9:517-531 (2008)).

[0041] Based primarily on amino acid sequence homology, studies have defined numerous subfamilies of the Ras superfamily, often designated in abbreviated terms based on the most commonly studied member of the class.

[0042] The GTP-binding domains of one subfamily of the Ras superfamily, which share substantial sequence homology, are commonly referred to as the Ras family or Ras.

[0043] There are four isoforms of Ras proteins expressed from three different genes: H-Ras (Harvey sarcoma viral oncogene), N-Ras (neuroblastoma oncogene), and the splice variants K-Ras4A and K-Ras4B (Kirsten sarcoma viral oncogene) (see Karnoub et al., supra).

[0044] Another subfamily of the Ras superfamily with substantial sequence homology to the GTP-binding domain is commonly referred to as the Rho family, and includes proteins and groups of proteins designated Rho, Rac, and Cdc42.

[0045] Ras functions and pathways All Ras isoforms share sequence identity in all regions involved in GDP / GTP binding, GTPase activity, and effector interactions, suggesting functional redundancy. However, studies have clearly demonstrated that each Ras isoform functions in a unique manner distinct from other Ras proteins in normal physiological processes and pathogenesis (Quinlan et al., Future Oncol., 5:105-116 (2009)).

[0046] Ras proteins cycle between "on" and "off" configurations, conferred by the binding of GTP and GDP, respectively. Under physiological conditions, the transition between these two states is controlled by guanine nucleotide exchange factors (GEFs), which promote Ras protein activation by stimulating the exchange of GDP for GTP, and by GTPase-activating proteins (GAPs), which accelerate Ras-mediated hydrolysis of GTP to GDP.

[0047] Several cell surface receptors activate Ras, including receptor tyrosine kinases (RTKs), growth factor receptors, cytokine receptors, and integrins.

[0048] Upon activation, Ras initiates signaling in the "MAPK pathway" (also called the Ras-RAF-MEK-MAPK / ERK pathway) that influences cell growth, differentiation, proliferation, apoptosis, and migration, and is associated with other molecular pathways, including phosphoinositide 3-kinase (PI3K), Rac1 GEF, and Ral-guanine nucleotide dissociation stimulator (GDS).

[0049] The MAPK pathway functions through a series of interactions between kinases. When activated by Ras in the "on" GTP-bound state, MAPK kinase kinases (MAPK3), such as Raf, MLK, or TAK, phosphorylate and activate MAPK kinases, such as MEK, which in turn phosphorylate and increase the activity of one or more MAPKs, such as ERK1 / 2. PI3K is part of the PI3K / AKT / mTOR pathway, which controls intracellular signaling important for several cellular functions, including survival, anti-apoptosis, and cell cycle regulation.

[0050] Ras dysfunction is causally linked to important diseases and disease processes Ras and its downstream pathways, including MAPK, have been extensively studied and are causally associated with a variety of diseases, including certain cancers, inflammatory diseases, Ras-associated autoimmune leukocyte proliferative disorders, and certain rasopathy.

[0051] There are multiple distinct pathways for aberrant Ras activation, including mutational activation of Ras itself, hyperactivation of the wild-type protein via upstream signaling, and loss of GAP function required to terminate the protein's activity.

[0052] The literature suggests that 1 million deaths per year are attributable to K-Ras mutations alone. (Frank McCormick. “K-Ras protein as a drug target.” Journal of Molecular Medicine (Berlin) 2016:94:253-258)

[0053] Ras is well documented as an oncogene. Ras oncogenes can initiate cancer in model organisms. Microinjection studies with antibodies that block Ras activity or specific mutant alleles of Ras; ablation of K-Ras in mouse models of lung adenocarcinoma or pancreatic cancer; and ablation of H-Ras all result in tumor regression in mouse models.

[0054] Approximately 30% of human cancers (Prior IA, Lewis PD, Mattos C. Cancer Res. 2012 May 15;72(10):2457-67) harbor mutated Ras proteins, with the most frequent mutations at residues G12, G13, and Q61. These oncogenic mutations result in the accumulation of GTP-bound Ras, leading to impaired GTP hydrolysis and increased activation of Ras-dependent downstream effector pathways.

[0055] Table 1 summarizes recent data on the frequency of K-Ras and N-Ras mutations in a non-exhaustive, but illustrative, list of human malignancies. [Table 1]

[0056] Ras mutations, and in some cases Ras hyperactivation, have been implicated in a wide range of critical cancer-related processes in the literature, including cell proliferation, DNA checkpoint integrity, clonal selection associated with replication stress, suppression of apoptosis, metabolic reprogramming, autophagy, microenvironment remodeling, immune response evasion, and metastatic processes. The detailed mechanisms, interdependencies, and frequency of these effects across various tumor types and stages of cancer development remain to be comprehensively elucidated.

[0057] Proliferative effects associated with oncogenic Ras in the literature include transcriptional upregulation of growth factors; upregulation of growth factor receptor expression; upregulation of proliferation-promoting integrins and downregulation of those associated with cytostasis; upregulation of transcription factors required for cell cycle entry; acceleration through cell cycle transitions; downregulation of antiproliferative TGFβ signaling; and suppression of cyclin-dependent kinase inhibitors.

[0058] MAPK signaling has been shown to enhance the expression of programmed death-ligand 1 (PD-L1) in KRas-mutated lung cancer cells, and Ras mutations are therefore associated with suppressed immune responses to cancer. (Sumimoto et al., PLOS One 2016 November 15; DOI: 10.1371 / journal.pone.0166626) Anti-PD-1 and anti-PD-L1 monoclonal antibodies have demonstrated clinical activity against tumors, including non-small cell lung cancer.

[0059] Ras has also been implicated in the pathogenesis of various pathological inflammatory conditions through the MAPK pathway. In addition to ERK1 / 2, MAPK ERK5, c-Jun N-terminal kinase (JNK), and p38 isoforms have been shown to be involved in inflammatory responses (Huang, et al. 2010, Protein Cell, 1(3), 218-226).

[0060] Ras is causally linked to inflammatory diseases, including the most common cause of disability (Hootman JM, Brault MW, Helmick CG, Theis KA, Armour BS. Prevalence and most common causes of disability among adults - United States 2005, MMWR, 2009, 58(16):421-6), rheumatoid arthritis (Abreu JR, de Launay D, Sanders ME, Grabiec AM, Sande van de MG, Tak PP, Reedquist KA: The Ras guanine nucleotide exchange factor RasGRF1 promotes matrix metalloproteinase-3 production in rheumatoid arthritis synovial tissue. Arthritis Res Ther. 2009, 11:R121-10.1186 / ar2785); and atherosclerosis (Fonarow G (2003), Cleve. Clin. J. Med. 70:431-434); inflammatory bowel diseases (IBD) such as Crohn's disease (Ignacio CS, Sandvik AK, Bruland T, Andreu-Ballester JC, J. Crohns Colitis, 2017 Mar 16. doi:10); ulcerative colitis, spondyloarthropathy, idiopathic pulmonary fibrosis, juvenile arthritis, psoriasis, psoriatic arthritis, etc.

[0061] Ras is causally linked to Ras-associated autoimmune leukoproliferative disorder, a non-malignant clinical syndrome first identified in a subset of patients with presumed autoimmune lymphoproliferative syndrome (ALPS). (Katherin Calvo, et al. "JMML and RALD (Ras-related autoimmune leukoproliferative disorder): common genetic etiology yet clinically distinct entities," Blood, 2015 Apr 30;125(18):2753-2758)

[0062] Aberrant Ras signaling is causally involved in a family of rasopathy including neurofibromatosis type 1, Noonan syndrome, and Costello syndrome.

[0063] Ras as a therapeutic molecular target Interference with the signaling of Ras superfamily members in cell-based and animal models of the aforementioned diseases modulates the disease process.

[0064] Therefore, Ras superfamily proteins, especially Ras and downstream pathway elements, have long been discussed as theoretical molecular targets for the development of targeted therapies. In theory, molecules that could interfere with such Ras signaling could function as therapeutic agents in diseases associated with aberrant Ras signaling.

[0065] Theoretically, it was recognized that a mechanism for downregulating aberrant Ras signaling could be to interfere with one or more steps in the Ras signaling process that involve GTP binding in a way that traps GTP in a configuration other than the "on" configuration. However, while this was a theoretical concept based on two widely accepted observations, it was also long recognized by the scientific community that it would not be possible to achieve.

[0066] GTP and GDP are known to bind to the GTP-binding domain of Ras with affinities in the one- to two-digit picomolar range.

[0067] Intracellular concentrations of GTP are known to exceed this range substantially.

[0068] The widely accepted finding of the affinity of GTP and GDP for the GTP-binding domain of Ras in the one- to two-picomolar range was determined by kinetic and filter-binding measurements between Ras and radiolabeled GDP and GTP (Feuerstein J, Kalbitzer HR, John J, Goody RS, Wittinghofer A. Eur. J. Biochem., 1987 Jan 2, 162(1):49-55; and John J, Sohmen R, Feuerstein J, Linke R, Wittinghofer A, Goody RS. Biochemistry, 1990 Jun 26, 29(25):6058-65).

[0069] Consistent with, and often citing, these findings, the GTP-binding domain of Ras has been widely accepted and reported as "undruggable" in prestigious journal articles, reviews, and monographs (Papke B, Der CJ., Science, 2017 Mar 17, 355(6330):1158-1163; Stephen AG, Esposito D, Bagni RK, McCormick F, Cancer Cell, 2014 Mar 17, 25(3):272-81; and Ostrem JM, Shokat KM, Nat. Rev. Drug Discov., 2016 Nov, 15(11):771-785).

[0070] Therefore, research into targeted Ras therapeutics has focused on domains of the Ras protein other than the GTP-binding site. These include, for example, farnesyltransferase inhibitors (FTIs), which prevent Ras binding to the inner side of the plasma membrane, and molecules that compete with the interaction of Ras with the exchange factor SOS or downstream effectors.

[0071] Therefore, it has been thought that it would be impossible to develop molecules to compete with GTP binding to the GTP-binding domain of Ras, however, compounds that do so would fill a need in the field.

[0072] Rho family functions and pathways The Rho subfamily of the Ras superfamily currently includes approximately 22 proteins, most of which scientists have divided into subgroups, including those commonly referred to as Cdc42, Rac, and Rho. (Boureux A, Vignal E, Faure S, Fort P (2007). "Evolution of the Rho family of ras-like GTPases in eukaryotes." Mol Biol Evol 24(1):203-16)

[0073] The three most commonly studied members of the Rho subfamily are Cdc42, Rac1, and RhoA.

[0074] The Cdc42 group includes Cdc42, TC10, TCL, Chip, and Wrch-1.

[0075] The Rac group includes Rac1, Rac2, Rac3, and RhoG.

[0076] The RhoA group includes RhoA, RhoB, and RhoC.

[0077] Other Rho subfamily GTPases that are not included in the Cdc42, Rac, or Rho groups include RhoE / Rnd3, RhoH / TTF, Rif, RhoBTB1, RhoBTB2, Miro-1, Miro-2, RhoD, Rnd1, and Rnd2.

[0078] Like other Ras superfamily proteins, Rho subfamily GTPases cycle between "on" and "off" configurations, conferred by GTP and GDP binding, respectively. Under physiological conditions, the transition between these two states is regulated by guanine nucleotide exchange factors (GEFs), which promote activation of Rho subfamily proteins by stimulating GDP release and GTP binding, and by GTPase-activating proteins (GAPs), which accelerate the hydrolysis of GTP to GDP via Rho subfamily members. Guanine nucleotide dissociation inhibitor (GDI) proteins form large complexes with Rho proteins, helping to prevent their diffusion into the membrane and cytosol, thus functioning as anchors and enabling strict spatial control of Rho activation.

[0079] Rho subfamily members are intracellular proteins that affect numerous downstream pathways broadly involved in cytoskeletal organization, cell polarity, migration, transcription, and proliferation, as well as membrane and vesicle trafficking, the cell cycle, microtubule stability, actin membrane binding, actin polymerization, myosin phosphorylation, API-dependent gene expression, cell adhesion, cell contractility, cell adhesion, and MTOC orientation (Martin Schwartz, "Rho Signaling at a Glance," Journal of Cell Science, 2004:(117:pp.5457-5458). and (Bustelo XR, Sauzeau V, Berenjeno IM (2007) "GTP-binding proteins of the Rho / Rac family: regulation, effectors, and functions in vivo," BioEssays, 29 (4):356-370).

[0080] Dysfunction of the Rho family is causally linked to important diseases. Rho subfamily GTPases have been reported to contribute to most stages of cancer development and progression, including the acquisition of unlimited proliferative potential, survival and avoidance of apoptosis, angiogenesis, tissue invasion, motility, and the establishment of metastasis. (Matteo Parri and Paolo Chiarugi. "Rac and Rho GTPases in Cancer Cell Motility Control." Cell Communication and Signaling. 2010(8:23))

[0081] High levels of Rho subfamily proteins are frequently associated with human tumors. High RhoA levels are associated with human liver, skin, colon, ovarian, bladder, stomach, esophageal squamous cell, testicular, and breast cancers. High RhoB, C, or H levels are associated with breast, squamous cell, pancreatic, breast, liver, ovarian, head and neck, prostate, non-small cell lung, and stomach cancers, as well as melanoma metastasis. High Rac1 levels are associated with human testicular, stomach, breast, and squamous cell carcinomas. High Rac2 or Rac3 levels are associated with breast, colon, head and neck, and squamous cell carcinomas. (Matteo Parri and Paolo Chiarugi. “Rac and Rho GTPases in Cancer Cell Motility Control.” Cell Communication and Signaling. 2010(8:23). Gain-of-function mutations such as P29S in Rac1 have been detected in melanoma, breast, and head and neck cancers. (Alan JK, Lundquist EA. Mutationally activated Rho GTPases in cancer. Small GTPases. 2013Jul-Sep;4(3):159-63)

[0082] Unlike Ras proteins, which are frequently mutated in cancer (approximately 30%), Rho subfamily proteins themselves are generally not mutated in cancer. Rather, aberrant activity of Rho subfamily proteins in cancer appears to result from overexpression of these proteins or aberrant regulation of molecules that control their activity, such as activation or overexpression of GEFs and inactivation or loss of GAPs or GDIs (Alan JK, Lundquist EA. Mutationally activated Rho GTPases in cancer. Small GTPases. 2013 Jul-Sep;4(3):159-63).

[0083] Interactions between Rac and Rho proteins are thought to regulate certain forms of mesenchymal and amoeboid cell motility associated with cancer.

[0084] Rho subfamily-related kinases (ROCK1 and ROCK2) have been implicated as mediators of multiple fibrotic processes, including those associated with idiopathic pulmonary fibrosis. (Knipe RS, Tager EM, and Liao JK. “The Rho kinases: critical mediators of multiple profibrotic processes and rational targets for new therapies for pulmonary fibrosis.” Pharmacol Rev. 2015 67(1):103-17.)

[0085] Rho family members as therapeutic molecular targets Given their role in disease processes, Rho subfamily members have been identified as potential therapeutic molecular targets.

[0086] Rho subfamily members have been identified as potential therapeutic molecular targets in cancer.

[0087] Rho subfamily members have been identified as potential therapeutic molecular targets in fibrotic diseases. Summary of the Invention

[0088] The affinity of GTP for the GTP-binding domain of K-Ras using scintillation proximity assay (SPA) and microscale thermophoresis (MST) is measured and disclosed herein for the first time. These methods were not available when Wittinghofer and colleagues (see above) undertook their work.

[0089] SPA and MST studies have shown, and are disclosed herein, that the affinity of GTP for the GTP-binding domain of K-Ras across wild-type and mutant K-Ras ranges from 100 to 465 nanomolar, leading to the novel and unexpected conclusion that compounds, such as small molecules, can be discovered that bind to the GTP-binding domain of Ras and compete with GTP binding to Ras.

[0090] Provided herein are novel cell-free assays for the identification of small molecules that bind to the GTP-binding domain and compete with GTP binding to, for example, wild-type KRas, KRas G12D mutant, KRas G12C mutant, KRas Q61H mutant, KRas G12D / Q61H double mutant, KRas G12C / Q61H double mutant, Rac1, and RhoA proteins.

[0091] Utilizing this assay as a screening and analytical tool provides over 1000 small molecules that competitively bind to the GTP-binding domain of Ras, thereby validating the significance of novel and unexpected binding affinity findings. Provided herein are methods for testing the affinity of compounds for the GTP-binding domain of Ras, including novel assays.

[0092] Using this assay, it has been demonstrated that over 1000 small molecules provided herein also bind competitively with GTP to the GTPase-binding domains of both Rac and Rho. Provided herein are methods for testing the affinity of compounds for the GTP-binding domains of Rac and Rho, including novel assays.

[0093] It is also demonstrated herein in cell-based assays that some of these molecules inhibit activation of the MAPK pathway and downregulate the growth of various human tumors.

[0094] It is further demonstrated herein in cell-based assays that some of these molecules downregulate the release of pro-inflammatory cytokines.

[0095] It is also demonstrated herein in cell-based assays that some of these molecules inhibit activation of the MAPK pathway and downregulate the growth of various human tumors.

[0096] It is further demonstrated herein in cell-based assays that some of these molecules downregulate the release of pro-inflammatory cytokines.

[0097] It is also demonstrated herein in cell-based assays that some of these molecules inhibit activation of the MAPK pathway and downregulate the growth of various human tumors.

[0098] It is further demonstrated herein in cell-based assays that some of these molecules downregulate the release of pro-inflammatory cytokines.

[0099] It has also been discovered and disclosed herein that certain amino acids in the GTP-binding domain of Ras enable previously unexpected competitive binding between compounds, such as small molecules, and GTP to that domain. These include the following amino acids: Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, and Mg202, which are also required for GTP binding. They also include the amino acid Gln61.

[0100] It has also been discovered and disclosed herein that certain amino acids in the GTP-binding domain of Rac1 enable previously unexpected competitive binding between compounds, such as small molecules, and GTP to that domain, including the following amino acids: Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, and Mg202, which is also required for GTP binding.

[0101] It has also been discovered and disclosed herein that certain amino acids in the GTP-binding domain of RhoA enable previously unexpected competitive binding between compounds, such as small molecules, and GTP to that domain, including the following amino acids: Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, and Mg202, which is also required for GTP binding.

[0102] Thus, provided herein are methods for inhibiting the function of Ras, comprising administering to a subject a compound that competitively binds to the GTP-binding domain of Ras. In one embodiment, the compound used in the method has a binding affinity (K d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Ras of less than 1 μM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Ras of less than 500 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Ras of less than 465 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Ras of less than 270 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Ras of less than 200 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Ras of less than 150 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Ras of less than 100 nM. d In one embodiment, the method for inhibiting the function of Ras has a binding affinity (K) of less than 465 nM. d In one embodiment, a method of inhibiting the function of Ras includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras with a binding affinity (K) of less than 270 nM. dIn one embodiment, a method of inhibiting the function of Ras includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras with a binding affinity (K) of less than 10 μM. d In one embodiment, a method for inhibiting Ras function includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147, or Mg202 in the highly conserved GTP-binding domain of Ras. In one embodiment, a method for inhibiting Ras function includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ser17, or Mg202 in the highly conserved GTP-binding domain of Ras. d In one embodiment, a method of inhibiting the function of Ras includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras with a binding affinity (K) of less than 270 nM. dIn one embodiment, a method of inhibiting the function of Ras includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras with a binding affinity (K) of less than 10 μM. d The present invention includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the highly conserved GTP-binding domain of Ras.

[0103] In the assays described herein, e.g., cell-free assays, the compounds used in the methods inhibit Ras and have an IC of less than 10 μM. 50 In one embodiment, the compound used in the method inhibits Ras and has an IC value of less than 1 μM. 50 In one embodiment, the compound used in the method inhibits Ras and has an IC value of less than 500 nM. 50 In one embodiment, the compound used in the method inhibits Ras and has an IC value of less than 465 nM. 50 In one embodiment, the compound used in the method inhibits Ras and has an IC value of less than 270 nM. 50 In one embodiment, the compound used in the method inhibits Ras and has an IC value of less than 200 nM. 50 In one embodiment, the compound used in the method inhibits Ras and has an IC value of less than 150 nM. 50 In one embodiment, the compound used in the method inhibits Ras and has an IC value of less than 100 nM. 50In one embodiment, the compound used in the method inhibits Ras with greater than 25% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Ras with greater than 50% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Ras with greater than 75% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Ras with greater than 80% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Ras with greater than 85% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Ras with greater than 90% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Ras with greater than 95% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Ras with greater than 99% inhibition at 20 μM. In one embodiment, a method of inhibiting the function of Ras comprises binding to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras and having a corresponding IC of less than 465 nM. 50 In one embodiment, a method for inhibiting Ras function includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras and has a corresponding IC value of less than 270 nM. 50In one embodiment, a method for inhibiting Ras function includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the highly conserved GTP-binding domain of Ras and has a corresponding IC value of less than 10 μM. 50 In one embodiment, a method for inhibiting Ras function comprises administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the highly conserved GTP-binding domain of Ras and inhibits Ras with greater than 50% inhibition at 20 μM. In one embodiment, a method of inhibiting the function of Ras comprises binding to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras and having a corresponding IC of less than 465 nM. 50In one embodiment, a method for inhibiting Ras function includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras and has a corresponding IC value of less than 270 nM. 50 In one embodiment, a method for inhibiting Ras function includes administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the highly conserved GTP-binding domain of Ras and has a corresponding IC value of less than 10 μM. 50 In one embodiment, a method for inhibiting Ras function comprises administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the highly conserved GTP-binding domain of Ras and inhibits Ras with greater than 50% inhibition at 20 μM.

[0104] In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In one embodiment, the Ras is HRAS, KRAS, or NRAS. In one embodiment, the Ras is HRAS. In one embodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. In another embodiment, the Ras is a mutant form of Ras described herein.

[0105] Also provided herein are methods for inhibiting Rho function, comprising administering to a subject a compound that competitively binds to the GTP-binding domain of Rho. In one embodiment, the compound used in the method has a binding affinity (K) for the GTP-binding domain of Rho of less than 10 μM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rho of less than 1 μM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rho of less than 500 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rho of less than 270 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rho of less than 200 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rho of less than 150 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rho of less than 130 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rho of less than 100 nM.d In one embodiment, the method for inhibiting Rho function comprises inhibiting Rho with a binding affinity (K) of less than 270 nM. d In one embodiment, a method for inhibiting the function of Rho includes administering to a subject a compound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho with a binding affinity (K) of less than 130 nM. d In one embodiment, a method for inhibiting the function of Rho includes administering to a subject a compound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho with a binding affinity (K) of less than 10 μM. d The present invention includes administering to a subject a compound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the highly conserved GTP-binding domain of Rho.

[0106] In the assays described herein, e.g., cell-free assays, the compounds used in the methods inhibit Rho and have an IC of less than 10 μM. 50 In one embodiment, the compound used in the method inhibits Rho and has an IC value of less than 1 μM. 50 In one embodiment, the compound used in the method inhibits Rho and has an IC value of less than 500 nM. 50 In one embodiment, the compound used in the method inhibits Rho and has an IC value of less than 270 nM. 50In one embodiment, the compound used in the method inhibits Rho and has an IC value of less than 200 nM. 50 In one embodiment, the compound used in the method inhibits Rho and has an IC value of less than 150 nM. 50 In one embodiment, the compound used in the method inhibits Rho and has an IC value of less than 130 nM. 50 In one embodiment, the compound used in the method inhibits Rho and has an IC value of less than 100 nM. 50 In one embodiment, the compound used in the method inhibits Rho with greater than 25% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rho with greater than 50% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rho with greater than 75% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rho with greater than 80% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rho with greater than 85% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rho with greater than 90% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rho with greater than 95% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rho with greater than 99% inhibition at 20 μM. In one embodiment, a method of inhibiting the function of Rho comprises binding to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho and having a corresponding IC of less than 270 nM. 50In one embodiment, a method for inhibiting Rho function includes administering to a subject a compound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho and has a corresponding IC value of less than 130 nM. 50 In one embodiment, a method for inhibiting Rho function includes administering to a subject a compound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the highly conserved GTP-binding domain of Rho and has a corresponding IC value of less than 10 μM. 50 In one embodiment, a method for inhibiting Rho function comprises administering to a subject a compound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the highly conserved GTP-binding domain of Rho and inhibits Rho with greater than 50% inhibition at 20 μM.

[0107] In one embodiment, Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3 or CDC42. In one embodiment, Rho is RHOA. In another embodiment, Rho is a mutant form of Rho described herein.

[0108] Also provided herein are methods for inhibiting the function of Rac, comprising administering to a subject a compound that competitively binds to the GTP-binding domain of Rac. In one embodiment, the compound used in the method has a binding affinity (K d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rac of less than 1 μM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rac of less than 500 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rac of less than 270 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rac of less than 200 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rac of less than 170 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rac of less than 150 nM. d In one embodiment, the compound used in the method has a binding affinity (K) to the GTP-binding domain of Rac of less than 100 nM. d In one embodiment, the method of inhibiting the function of Rac has a binding affinity (K) of less than 270 nM. d 119, or Mg202 in the GTP-binding domain of Rac with a binding affinity (K) of less than 170 nM. dIn one embodiment, a method of inhibiting the function of Rac includes administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac with a binding affinity (K) of less than 10 μM. d The present invention includes administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the highly conserved GTP-binding domain of Rac.

[0109] In the assays described herein, e.g., cell-free assays, the compounds used in the methods inhibit Rac and have an IC of less than 10 μM. 50 In one embodiment, the compound used in the method inhibits Rac and has an IC value of less than 1 μM. 50 In one embodiment, the compound used in the method inhibits Rac and has an IC value of less than 500 nM. 50 In one embodiment, the compound used in the method inhibits Rac and has an IC value of less than 270 nM. 50 In one embodiment, the compound used in the method inhibits Rac and has an IC value of less than 200 nM. 50 In one embodiment, the compound used in the method inhibits Rac and has an IC value of less than 170 nM. 50 In one embodiment, the compound used in the method inhibits Rac and has an IC value of less than 150 nM. 50 In one embodiment, the compound used in the method inhibits Rac and has an IC value of less than 100 nM. 50In one embodiment, the compound used in the method inhibits Rac with greater than 25% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rac with greater than 50% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rac with greater than 75% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rac with greater than 80% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rac with greater than 85% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rac with greater than 90% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rac with greater than 95% inhibition at 20 μM. In one embodiment, the compound used in the method inhibits Rac with greater than 99% inhibition at 20 μM. In one embodiment, a method of inhibiting the function of Rac comprises inhibiting one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Ras and having a corresponding IC of less than 270 nM. 50 In one embodiment, a method for inhibiting the function of Rac includes administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac and has a corresponding IC value of less than 270 nM. 50In one embodiment, a method for inhibiting the function of Rac includes administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Ras and has a corresponding IC value of less than 170 nM. 50 In one embodiment, a method for inhibiting the function of Rac includes administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac and has a corresponding IC value of less than 170 nM. 50 In one embodiment, a method for inhibiting Rac function includes administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the highly conserved GTP-binding domain of Rac and has a corresponding IC value of less than 10 μM. 50 In one embodiment, a method for inhibiting the function of Rac comprises administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the highly conserved GTP-binding domain of Rac and inhibits Rho with greater than 99% inhibition at 20 μM.

[0110] In one embodiment, Rho is Rac. In one embodiment, Rac is RAC1; RAC2; RAC3 or RHOG. In one embodiment, Rac is RAC1. In another embodiment, Rac is a mutant form of Rac described herein.

[0111] In one embodiment, provided herein is a method for treating or preventing cancer by administering a compound that inhibits GTP binding to the GTP-binding domain of one or more members of the Ras superfamily. In one embodiment, provided herein is a method for treating or preventing inflammation by administering a compound that inhibits GTP binding to the GTP-binding domain of one or more members of the Ras superfamily. In one embodiment, provided herein is a method for treating or preventing rasopathy by administering a compound that inhibits GTP binding to the GTP-binding domain of one or more members of the Ras superfamily. In one embodiment, provided herein is a method for treating or preventing fibrotic diseases by administering a compound that inhibits GTP binding to the GTP-binding domain of one or more members of the Ras superfamily. In one embodiment, provided herein is a method for treating or preventing cancer by administering a compound that inhibits GTP binding to the GTP-binding domain of Ras. In one embodiment, provided herein is a method for treating or preventing inflammation by administering a compound that inhibits GTP binding to the GTP-binding domain of Ras. In one embodiment, provided herein is a method for treating or preventing rasopathy by administering a compound that inhibits GTP binding to the GTP-binding domain of Ras. In one embodiment, provided herein is a method for treating or preventing Ras-associated autoimmune leukocyte proliferative disorders by administering a compound that inhibits GTP binding to the GTP-binding domain of Ras. In one embodiment, provided herein is a method for treating or preventing fibrotic diseases by administering a compound that inhibits GTP binding to the GTP-binding domain of Ras. In one embodiment, provided herein is a method for treating or preventing cancer by administering a compound that inhibits GTP binding to the GTP-binding domain of Rho. In one embodiment, provided herein is a method for treating or preventing inflammation by administering a compound that inhibits GTP binding to the GTP-binding domain of Rho. In one embodiment, provided herein is a method for treating or preventing rasopathy by administering a compound that inhibits GTP binding to the GTP-binding domain of Rho.In one embodiment, provided herein is a method for treating or preventing a fibrotic disease by administering a compound that inhibits GTP binding to the GTP-binding domain of Rho. In one embodiment, provided herein is a method for treating or preventing cancer by administering a compound that inhibits GTP binding to the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing inflammation by administering a compound that inhibits GTP binding to the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing rasopathy by administering a compound that inhibits GTP binding to the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing a fibrotic disease by administering a compound that inhibits GTP binding to the GTP-binding domain of Rac.

[0112] Provided herein are compounds that bind to the GTP-binding domain of Ras and compete with GTP binding to Ras. In one embodiment, the compounds also inhibit the phosphorylation of MAPK, particularly MAPK1 / 2, cell proliferation, and secretion of IL-6 or TNF-α cytokines. As such, the compounds provided herein are useful in compositions and methods for treating cancer, inflammatory diseases, Ras-associated autoimmune leukocyte proliferative disorders, and rasopathy.

[0113] Provided herein are compounds that bind to the GTP-binding domain of Rac and compete with GTP binding to Rac. In one embodiment, the compounds also inhibit the MAPK signaling pathway. In one embodiment, the compounds also inhibit the ROCK signaling pathway. Therefore, the compounds provided herein are useful in compositions and methods for treating cancer, inflammatory diseases, and fibrotic diseases.

[0114] Provided herein are compounds that bind to the GTP-binding domain of Rho and compete with GTP binding to Rho. In one embodiment, the compounds also inhibit the MAPK signaling pathway. In one embodiment, the compounds also inhibit the ROCK signaling pathway. As such, the compounds provided herein are useful in compositions and methods for treating cancer, inflammatory diseases, and fibrotic diseases.

[0115] In one embodiment, the compounds provided herein inhibit GTP binding to one or more members of the Ras superfamily. In one embodiment, the compounds provided herein inhibit GTP binding to Ras. In one embodiment, the compounds provided herein inhibit GTP binding to Rho. In one embodiment, the compounds provided herein inhibit GTP binding to Rac. In one embodiment, the compounds provided herein inhibit GTP binding to Ras and Rho. In one embodiment, the compounds provided herein inhibit GTP binding to Ras and Rac. In one embodiment, the compounds provided herein inhibit GTP binding to Rho and Rac. In one embodiment, the compounds provided herein inhibit GTP binding to Ras, Rho, and Rac.

[0116] In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 2000 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1750 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1500 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1250 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1000 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 750 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 665 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 500 daltons. In another embodiment, the compounds used in the methods and compositions provided herein contain an oxadiazole, thiadiazole, or triazole moiety. In another embodiment, the compound used in the methods and compositions provided herein contains a 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 2-acylaminothiazole, 2-(pyridin-2-yl)pyrimidin-4-amine, 2-(pyridin-2-yl)pyrimidin-4-ol, 2-(pyridin-2-yl)pyrimidin-4-(1H)-one, 2-(pyridin-2-yl)pyrimidin-4(3H)-one, 2-(pyridin-2-yl)pyrimidin-4(1H)-imine, or 2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety.In another embodiment, the compound used in the methods and compositions provided herein is 2-(pyridin-2-yl)pyrimidin-4-amine, 2-(pyridin-2-yl)pyrimidin-4-ol, 2-(pyridin-2-yl)pyrimidin-4-(1H)-one, 2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one, 2-(imidazol-2-yl)pyrimidin-4(1H)-one, 2-(imidazol-2-yl)pyrimidin-4-amine, 2-(imidazole 2-(imidazol-4-yl)pyrimidin-4(3H)-imine, 2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol, 2-(imidazol-4-yl)pyrimidin-4(3H)-one, 2-(imidazol-4-yl)pyrimidin-4(1H)-one, 2-(imidazol-4-yl)pyrimidin-4-amine, 2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or 2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety. [Brief explanation of the drawings]

[0117] [Figure 1] The crystal structure of GDP bound to the GTP-binding site of KRas is illustrated (PDB code: 4epr). [Figure 2] 1 illustrates the compounds disclosed herein binding to the guanosine binding region of the GTP binding site of KRas as determined through molecular modeling of the compounds disclosed herein in the KRas crystal structure PDB code: 4epr. [Figure 3] 1 illustrates the compounds disclosed herein binding to the metal region of the GTP binding site of KRas as determined through molecular modeling of the compounds disclosed herein in the KRas crystal structure PDB code: 4epr. [Figure 4] 1 illustrates compounds disclosed herein binding to the guanosine binding region of an alternative Tyr32 configuration in the GTP binding site of KRas as determined through molecular modeling of compounds disclosed herein in the KRas crystal structure PDB code: 3gft. [Figure 5] KRas Crystal Structure PDB Code: 3gft depicts compounds disclosed herein binding to the metal domain of an alternative Tyr32 configuration in the GTP binding site of KRas as determined through molecular modeling of compounds disclosed herein. [Figure 6] 1 illustrates the compounds disclosed herein binding to the guanosine binding region of the GTP binding site of KRas as determined through molecular modeling of the compounds disclosed herein in the KRas crystal structure PDB code: 4epr. [Figure 7] 1 illustrates the compounds disclosed herein binding to the metal region of the GTP binding site of KRas as determined through molecular modeling of the compounds disclosed herein in the KRas crystal structure PDB code: 4epr. [Figure 8] 1 illustrates compounds disclosed herein binding to the guanosine binding region of an alternative Tyr32 configuration in the GTP binding site of KRas as determined through molecular modeling of compounds disclosed herein in the KRas crystal structure PDB code: 3gft. [Figure 9] KRas Crystal Structure PDB Code: 3gft depicts compounds disclosed herein binding to the metal domain of an alternative Tyr32 configuration in the GTP binding site of KRas as determined through molecular modeling of compounds disclosed herein. [Figure 10] KRas Crystal Structure PDB Code: 3gft depicts compounds disclosed herein binding to the metal domain of an alternative Tyr32 configuration in the GTP binding site of KRas as determined through molecular modeling of compounds disclosed herein. [Figure 11] KRas Crystal Structure PDB Code: 3gft depicts compounds disclosed herein binding to the metal domain of an alternative Tyr32 configuration in the GTP binding site of KRas as determined through molecular modeling of compounds disclosed herein. [Figure 12]KRas Crystal Structure PDB Code: 3gft depicts compounds disclosed herein binding to the metal domain of an alternative Tyr32 configuration in the GTP binding site of KRas as determined through molecular modeling of compounds disclosed herein. [Figure 13] 1 illustrates the compounds disclosed herein binding to the metal region of the GTP binding site of Rac-1 as determined through molecular modeling of the compounds disclosed herein in the Rac-1 crystal structure PDB code: 2p2l. [Figure 14] 1 illustrates the compounds disclosed herein binding to the metal region of the GTP binding site of Rac-1 as determined through molecular modeling of the compounds disclosed herein in the Rac-1 crystal structure PDB code: 2p2l. [Figure 15] 1 illustrates the compounds disclosed herein binding to the metal region of the GTP binding site of Rac-1 as determined through molecular modeling of the compounds disclosed herein in the Rac-1 crystal structure PDB code: 2p2l. [Figure 16] 1 illustrates the compounds disclosed herein binding to the metal region of the GTP binding site of Rho-A as determined through molecular modeling of the compounds disclosed herein in the Rho-A crystal structure PDB code: 5hpy. [Figure 17] 1 illustrates the compounds disclosed herein binding to the metal region of the GTP binding site of Rho-A as determined through molecular modeling of the compounds disclosed herein in the Rho-A crystal structure PDB code: 5hpy. [Figure 18] 1 illustrates the compounds disclosed herein binding to the metal region of the GTP binding site of Rho-A as determined through molecular modeling of the compounds disclosed herein in the Rho-A crystal structure PDB code: 5hpy.

[0118] 5. Detailed Description 5.1.Definition To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0119] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0120] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0121] As used herein, a "subject" is an animal, such as a mammal, including a human, such as a patient.

[0122] As used herein, biological activity refers to the in vivo activity of a compound or the physiological response that occurs upon in vivo administration of a compound, composition, or other mixture. Thus, biological activity encompasses the therapeutic effects and pharmacokinetic behavior of such compounds, compositions, and mixtures. Biological activity can be observed in in vitro systems designed to test for such activity.

[0123] As used herein, pharmaceutically acceptable derivatives of a compound include, but are not limited to, salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates, or hydrates. Such derivatives can be easily prepared by those skilled in the art using known methods for such derivatization. The resulting compounds can be administered to animals or humans without substantial toxic effects and are either pharmaceutically active or prodrugs. Pharmaceutically acceptable salts include amine salts, such as, but not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as, but not limited to, lithium, Salts of potassium and sodium; alkaline earth metal salts, including but not limited to, barium, calcium, and magnesium; transition metal salts, including but not limited to, zinc; and inorganic salts, including but not limited to, sodium hydrogen phosphate and disodium phosphate; also, salts of mineral acids, including but not limited to, hydrochlorides and sulfates; and salts of organic acids, including but not limited to, acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, mesylate, and fumarate. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids, and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of the formula C═C(OR), where R is alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl.Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of the formula C=C(OC(O)R), where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, 1 to about 10, or 1 to about 2, 3, or 4 solvent or water molecules.

[0124] As used herein, treatment refers to any procedure in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use to treat cancer, inflammation, or rhasopathy.

[0125] As used herein, amelioration of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any relief, whether permanent or temporary, lasting or transient, that can result from or be associated with administration of the composition.

[0126] As used herein, unless otherwise indicated, the terms "manage," "managing," and "management" include preventing the recurrence of a particular disease or disorder in a subject already afflicted with the disease or disorder and / or prolonging the time a subject afflicted with a disease or disorder remains in remission. These terms include modulating the threshold, onset, and / or duration of the disease or disorder, or altering the way a subject responds to a disease or disorder.

[0127] As used herein, IC 50 refers to the amount, concentration or dosage of a particular test compound that achieves 50% inhibition of a maximal response in an assay that measures such response.

[0128] As used herein, K drefers to the measured equilibrium dissociation constant between a compound (or ligand) and a protein (or binding domain of a protein).

[0129] As used herein, "Ras superfamily" refers to a protein superfamily of small guanosine triphosphatases (GTPases) consisting of five major families: Ras, Rho, Rab, Ran, and Arf, or variants thereof. Subfamilies of the five major families are also included, for example, the Rac subfamily of the Rho major family.

[0130] As used herein, "Ras" or "Ras family" or "Ras subfamily" or "Ras group" means DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; RRAS2, or mutants thereof.

[0131] As used herein, "Rho" or "Rho family" or "Rho subfamily" or "Rho group" means RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42, or variants thereof.

[0132] As used herein, "Rac" or "Rac family" or "Rac subfamily" or "Rac group" means RAC1; RAC2; RAC3; RHOG, or variants thereof.

[0133] As used herein, "GTP binding site" or "GTP binding domain" both refer to the region of a protein that binds GTP and the surrounding region of said protein to which another compound can bind, such binding blocking the ability of GTP to bind to said protein.

[0134] As used herein, "GDP-binding site" or "GDP-binding domain" both refer to the region of a protein that binds to GDP and the surrounding region of said protein to which another compound can bind, such binding blocking the ability of GDP to bind to said protein.

[0135] As used herein, "guanosine-binding region" means the region of a protein that is part of the GDP-binding domain or GTP-binding domain, which mediates the interaction with the guanosine moiety of GDP or GTP.

[0136] As used herein, "metal region" means a region of a protein that is close to the magnesium (Mg2O2) binding site and is part of the GDP- or GTP-binding domain.

[0137] As used herein, "alternative Tyr32 arrangement" means the arrangement of the GTP or GDP binding domain in the region of Tyr32 in the KRas crystal structure PDB code: 3gft compared to the KRas crystal structure PDB code: 4epr.

[0138] It should be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure or may be a mixture of stereoisomers or diastereomers. Thus, those skilled in the art will recognize that administration of the (R) form of a compound is equivalent to administration of the (S) form of a compound in the case of compounds that undergo epimerization in vivo.

[0139] As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities, as determined by standard analytical methods used by those skilled in the art to assess such purity, such as thin-layer chromatography (TLC), gel electrophoresis, high-performance liquid chromatography (HPLC), and mass spectrometry (MS), or sufficiently pure such that further purification does not detectably alter the enzymatic and biological activity of the substance. Methods for the purification of compounds to produce substantially chemically pure compounds are known to those skilled in the art. However, a substantially chemically pure compound may be a mixture of stereoisomers. In such cases, further purification may increase the specific activity of the compound. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chiral reverse-phase HPLC. When the compounds described herein contain an olefinic double bond or other center of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Likewise, all tautomers are intended to be included. For example, Formula VI may be represented by R 5 In the case of =H, the following three tautomeric structures are included but are not limited to: [ka]

[0140] As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is used as commonly understood by one of ordinary skill in the art.

[0141] As used herein, alkyl, alkenyl, and alkynyl carbon chains, unless otherwise specified, contain 1 to 20 carbons or 1 to 16 carbons and are straight or branched. Alkenyl carbon chains of 2 to 20 carbons, in certain embodiments, contain 1 to 8 double bonds, and alkenyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 double bonds. Alkynyl carbon chains of 2 to 20 carbons, in certain embodiments, contain 1 to 8 triple bonds, and alkynyl carbon chains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds. Exemplary alkyl, alkenyl, and alkynyl groups herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl, ethenyl, propenyl, butenyl, pentenyl, acetylenyl, and hexynyl. As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer to carbon chains having from about 1 or about 2 carbons up to about 6 carbons. As used herein, "alk(en)(yn)yl" refers to an alkyl group containing at least one double bond and at least one triple bond.

[0142] As used herein, "heteroalkyl" refers to one or more oxygen, sulfur (including S(=O) and S(=O) groups), or substituted or unsubstituted nitrogen atoms (-NR- and -N) inserted in a hydrocarbon chain. + refers to a straight-chain or branched aliphatic hydrocarbon group containing an RR- group wherein the nitrogen substituent(s) are alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, S(=O)R' or COR', where R' is alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, OY or -NYY', where Y and Y' are each independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, in one embodiment having 1 to about 20 atoms in the chain, and in another embodiment 1 to 12 atoms.

[0143] As used herein, "cycloalkyl" refers to a saturated mono- or polycyclic ring system of 3 to 10 carbon atoms in certain embodiments, and 3 to 6 carbon atoms in other embodiments; cycloalkenyl and cycloalkynyl refer to mono- or polycyclic ring systems containing at least one double bond and at least one triple bond, respectively. Cycloalkenyl and cycloalkynyl groups can contain 3 to 10 carbon atoms in certain embodiments, with cycloalkenyl groups containing 4 to 7 carbon atoms in further embodiments, and cycloalkynyl groups containing 8 to 10 carbon atoms in further embodiments. The ring systems of cycloalkyl, cycloalkenyl, and cycloalkynyl groups can be composed of one ring or two or more rings that can be joined together in a fused, bridged, or spiro-connected fashion. "Cycloalk(en)(yn)yl" refers to a cycloalkyl group containing at least one double bond and at least one triple bond. In some embodiments, the cycloalkyl ring is unsaturated or partially saturated.

[0144] As used herein, "carbocyclic" refers to a mono- or polycyclic ring system in which all of the atoms comprising the ring are carbon atoms, e.g., benzene or cyclopropane. In some embodiments, the carbocyclic ring is unsaturated or partially saturated.

[0145] As used herein, "substituted alkyl," "substituted alkenyl," "substituted alkynyl," "substituted cycloalkyl," "substituted cycloalkenyl," and "substituted cycloalkynyl" refer, respectively, to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl groups, substituted with one or more substituents, in certain embodiments 1 to 3 or 4 substituents, wherein the substituents are as defined herein and in one embodiment selected from Q.

[0146] As used herein, "aryl" refers to a monocyclic or polycyclic group containing 6 to 19 carbon atoms. Aryl groups include, but are not limited to, groups such as fluorenyl, substituted fluorenyl, phenyl, substituted phenyl, naphthyl, and substituted naphthyl.

[0147] As used herein, "heteroaryl" refers, in certain embodiments, to a monocyclic or polycyclic aromatic ring system having about 5 to 15 members, in which one or more, in one embodiment one to three, of the atoms in the ring system are heteroatoms that are atoms other than carbon, including, but not limited to, nitrogen, oxygen, or sulfur. The heteroaryl group may optionally be fused to a benzene ring. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, and isoquinolinyl.

[0148] As used herein, "heterocycloalkyl," "heterocyclyl," or "heterocyclic" refers to a monocyclic or polycyclic non-aromatic ring system, in one embodiment 3-10 members, in another embodiment 4-7 members, and in a further embodiment 5-6 members, in which one or more, and in certain embodiments 1-3, of the atoms in the ring system are heteroatoms that are atoms other than carbon, including, but not limited to, nitrogen, oxygen, or sulfur. In embodiments in which the heteroatom(s) is nitrogen, the nitrogen is optionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, acyl, guanidino, amidino, sulfonyl, or the nitrogen can be quaternized to form an ammonium group (substituents selected as described above). In some embodiments, the heterocyclic ring is saturated. In some embodiments, the heterocyclic ring is unsaturated or partially saturated.

[0149] As used herein, "substituted aryl," "substituted heteroaryl," and "substituted heterocyclyl" refer, respectively, to aryl, heteroaryl, and heterocyclyl groups, substituted with one or more substituents, in certain embodiments 1 to 3 or 4 substituents, wherein the substituents are as defined herein and in one embodiment selected from Q.

[0150] As used herein, "aralkyl" or "arylalkyl" refers to an alkyl group in which one of the alkyl's hydrogen atoms is replaced by an aryl group.

[0151] As used herein, "heteroaralkyl" refers to an alkyl group in which one of the alkyl's hydrogen atoms is replaced by a heteroaryl group.

[0152] As used herein, "halo," "halogen," or "halide" refers to F, Cl, Br, or I.

[0153] As used herein, a pseudohalide or pseudohalo group is a group that behaves substantially similarly to a halide. Such compounds can be used and treated in the same manner as halides. Pseudohalides include, but are not limited to, cyano, thiocyanate, selenocyanate, trifluoromethoxy, and azide.

[0154] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl, and 1-chloro-2-fluoroethyl.

[0155] As used herein, "haloalkoxy" refers to RO where R is a haloalkyl group.

[0156] As used herein, "carboxy" refers to the divalent group, --C(O)O--.

[0157] As used herein, "aminocarbonyl" refers to -C(O)NH2.

[0158] As used herein, "alkylaminocarbonyl" refers to -C(O)NHR where R is alkyl, including lower alkyl. As used herein, "dialkylaminocarbonyl" refers to -C(O)NR'R where R' and R are independently alkyl, including lower alkyl; and "carboxamido" refers to a group of formula -NR'COR where R' and R are independently alkyl, including lower alkyl.

[0159] As used herein, "arylalkylaminocarbonyl" refers to -C(O)NRR', where one of R and R' is aryl, including lower aryl, e.g., phenyl, and the other of R and R' is alkyl, including lower alkyl.

[0160] As used herein, "arylaminocarbonyl" refers to --C(O)NHR where R is aryl, including lower aryl, e.g., phenyl.

[0161] As used herein, "hydroxycarbonyl" refers to --COOH.

[0162] As used herein, "alkoxycarbonyl" refers to --C(O)OR where R is alkyl, including lower alkyl.

[0163] As used herein, "aryloxycarbonyl" refers to -C(O)OR where R is aryl, including lower aryl, e.g., phenyl.

[0164] As used herein, "alkoxy" and "alkylthio" refer to RO- and RS-, where R is alkyl, including lower alkyl.

[0165] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is aryl, including lower aryl, such as phenyl.

[0166] Where the number of any given substituent is not specified (e.g., "haloalkyl"), one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens.

[0167] As used herein, a "cyclic structure" can be a cycloalkyl, carbocyclic, heterocyclic, aryl, or heteroaryl group.

[0168] Where no substituent is specified (e.g., "aryl"), one or more substituents may be present. For example, "aryl" can include "substituted aryl" groups. In some embodiments, each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents, in one embodiment 1, 2, 3, or 4 substituents Q, each Q being independently selected from the group consisting of: (a) deuterium, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclyl (each of which may contain one or more, in one embodiment one, two, three, or four or more, substituents Q a and (c) -C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(NR a )NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c, -OC(=NR a )NR b R c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(=NR d )NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c (Each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl (each of which may contain one or more, in one embodiment one, two, three, or four, substituents Q a (iii) optionally substituted with R band R c together with the N atom to which they are attached, one or more, in one embodiment one, two, three, or four substituents Q a each Q is selected from the group consisting of a are independently: (a) deuterium, cyano, halo, and nitro; (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(NR e )NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(=NR e )NR f R g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(=NR h )NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NRf R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl. In some embodiments, two Q substituents together with the atom to which they are attached can form a fused ring system.

[0169] As used herein, any protecting group, amino acid, and other chemical abbreviations, unless otherwise indicated, are recognized abbreviations, consistent with their common usage, the IUPAC-IUB Commission on Biochemical Nomenclature (see (1972) Biochem. 11:942-944), or the IUPAC nomenclature of Organic Chemistry (Favre HA and Powell WH, Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013, Cambridge, UK: The Royal Society of Chemistry, 2013: Print ISBN 978-0-85404-182-4, PDF eISBN 978-1-84973-306-9, DOI 10.1039 / 9781849733069; Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979. Copyright 1979 IUPAC; and A Guide to IUPAC Nomenclature of Organic Compounds (Recommendations 1993), 1993, Blackwell Scientific publications, Copyright 1993 IUPAC).

[0170] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein to refer to a mammalian subject, such as a human subject, and in one embodiment, a human.

[0171] The terms "treat," "treating," and "treatment" are meant to include alleviating or arresting a disorder, disease, or condition, or one or more symptoms associated with a disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.

[0172] The terms "prevent," "preventing," and "prevention" are meant to include methods of delaying and / or preventing the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from contracting a disorder, disease, or condition; or reducing a subject's risk of contracting a disorder, disease, or condition.

[0173] The term "therapeutically effective amount" is intended to include an amount of a compound sufficient, when administered, to prevent or alleviate to some extent one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" also refers to an amount of a compound sufficient to elicit the biological or medical response in a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, physician, or clinician. A therapeutically effective amount of a compound provided herein can be administered in a single dose (i.e., a single dose administration) or divided and administered over time (i.e., sequential or multiple sub-dose administrations). Single dose administration, sequential administration, or multiple sub-dose administrations can be repeated, for example, to maintain the level of the compound in a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human.

[0174] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation and suitable for use in contact with the tissues or organs of human beings and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Remington: The Science and Practice of Pharmacy,22nd ed.;Loyd et al.,Eds.;The Pharmaceutical Press,2012;Handbook of Pharmaceutical Excipients,7th ed.;Rowe et al.,Eds.;The Pharmaceutical Press,2012;Handbook of Pharmaceutical Additives,3rd ed.;Ash and Ash Eds.;Synapse Information Resources,Inc.,2007;Pharmaceutical See Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC, 2009.

[0175] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0176] The term "weight percent" or "% by weight" refers to the weight of a particular component (e.g., an active compound or excipient) in a composition (e.g., a pharmaceutical composition) as a percentage of the total weight of the composition. Thus, the sum of the weight percentages of all components in a composition equals 100%.

[0177] The terms "active ingredient" and "active substance" refer to a compound administered to a subject, alone or in combination with one or more pharmaceutically acceptable excipients, to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease. As used herein, "active ingredient" and "active substance" may be an optically active isomer or isotopic variant of a compound described herein.

[0178] The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a chemical compound, or pharmaceutical composition thereof, that is administered to a subject to treat, prevent, or ameliorate one or more symptoms of a condition, disorder, or disease.

[0179] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 50% or greater, about 70% or greater, about 80% or greater, about 90% or greater, about 91% or greater, about 92% or greater, about 93% or greater, about 94% or greater, about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or about 99.8% or greater. In certain embodiments, the compound contains about 95% or greater of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the subject racemate.

[0180] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction in which a plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs of optical rotation (+) and (-) do not relate to the absolute configuration R and S of the molecule.

[0181] The term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, an "isotopic variant" of a compound is an isotope of hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., is non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), Phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), and iodine-127( 127 In certain embodiments, an "isotopic variant" of a compound is in a non-stable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), Fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33(33 P), sulfur-35( 35 S), chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I), and iodine-131( 131 In the compounds provided herein, any hydrogen may be, for example, an isotope of, for example, I), where feasible according to the judgment of one skilled in the art. 2 H or any carbon can be, for example, 13 C, or any nitrogen can be, for example, 15 N, and any oxygen 18 It is understood that the isotopic variant may be O. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of deuterium. In some embodiments, a pharmaceutically acceptable derivative of a compound is an isotopic variant.

[0182] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0183] The phrase "an isomeric variant thereof; or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable solvate thereof" has the same meaning as the phrase "an isomeric variant of the compound referenced therein; or a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable salt of an isomeric variant of the compound referenced therein; or a pharmaceutically acceptable solvate of the compound referenced therein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt of the compound referenced therein; or a pharmaceutically acceptable solvate of a compound referenced therein or a variant thereof or an isomeric variant of that variant."

[0184] 5.2. GTP-binding domain of RAS Data on the affinity of GTP for the GTP-binding domain of Ras The affinity of GTP for the GTP-binding domain of K-Ras using scintillation proximity assay (SPA) and microscale thermophoresis (MST) is measured and disclosed herein for the first time. These methods were not available when Wittinghofer and colleagues undertook their work.

[0185] SPA and MST studies have shown that the affinity of GTP for the GTP-binding domain of K-Ras via wild-type and mutant K-Ras is in the range of 100–465 nanomolar, as disclosed herein (see results in Table 2). This has led to the novel and unexpected conclusion that it is possible to discover compounds, such as small molecules, that bind to the GTP-binding domain of Ras and compete with GTP binding to Ras. SPA and MST studies performed on Rac-1 and Rho-A members of the Rho subfamily have shown that the affinity of GTP for the binding domain of these Rho subfamily members is in the range of 120–170 nanomolar (see results in Table 2). [Table 2]

[0186] For the SPA procedure, see Khawaja et al., "Scintillation proximity assay in lead discovery," Expert Opin. Drug Discov., 2008 Nov;3(11):1267-80. See the following references regarding MST technology: Wienken et al., Nature Communications (2010), Protein binding assays in biological liquids using MicroScale Thermophoresis; Jerabek-Willemsen et al., ASSAY and Drug Development Technologies (2011), Molecular interaction studies using MicroScale Thermophoresis; Lin et al., Cell (2012), Inhibition of basal FGF receptor signaling by dimeric Grb2; Seidel et al., Angewandte Chemie (2012), Label-Free MicroScale Thermophoresis discriminates sites and affinity of protein-ligand binding; Seidel et al., Methods (2012), MicroScale Thermophoresis quantifies biomolecular interactions under previously challenging conditions; Parker & Newstead, Nature (2014), Molecular basis of nitrate uptake by the plant nitrate transporter NRT1.1; and Jerabek-Willemsen et al., Journal of Molecular Structure (2014), MicroScale Thermophoresis: Interaction analysis and beyond.

[0187] Discovery of a small molecule that competes with GTP to bind to the GTP-binding domain of Ras Provided herein are assays for the identification of small molecules that compete with GTP to bind to the GTP-binding domain of Ras.

[0188] A useful and novel approach to drug discovery described herein is to identify small molecule inhibitors that compete with and block the interaction between GTP and GTP-binding proteins. By interacting with the GDP / GTP-binding site of a GTP-binding protein, the small molecule so identified can induce the GTP-binding protein into a GDP-bound or other inactive conformation, thus blocking the downstream signal transduction pathway of the GTP-binding protein.

[0189] The developed assay measures and quantifies the ability of small molecules tested in a cell-free system to compete for GTP or GDP binding, and can be used in small-scale or high-throughput screening (HTS) to screen compound libraries and support medicinal chemistry structure-activity relationship (SAR) efforts.

[0190] This is a competitive binding assay that involves immobilizing the protein on a solid phase, interacting with a small molecule drug candidate, and then competitive binding with a labeled native GTP or GDP ligand.

[0191] In one embodiment, a method is provided to test the ability of one or more compounds to bind to a GTP-binding domain and compete for GTP binding of one or more members of the Ras superfamily, comprising: a) expressing a Ras superfamily protein or its mutant as a tagged protein; b) contacting one or more compounds with the tagged protein, followed by incubation of the combination; c) adding labeled GTP or labeled GDP to each protein-compound combination, followed by incubating the resulting mixture; and d) measuring the amount of bound labeled GTP or bound labeled GDP A method is provided herein, comprising:

[0192] In one embodiment, the method further comprises, between steps a) and b): adding the tagged protein to one or more wells of a ligand-coated single- or multi-well plate and incubating the tagged protein.

[0193] In one embodiment of the method, one or more members of the Ras superfamily are Ras. In one embodiment of the method, Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In one embodiment of the method, Ras is HRAS, KRAS, NRAS, or a mutant thereof. In one embodiment of the method, Ras is HRAS or a mutant thereof. In one embodiment of the method, Ras is KRAS or a mutant thereof. In one embodiment of the method, Ras is NRAS or a mutant thereof.

[0194] In one embodiment of the method, the Ras superfamily protein is a KRras G12D mutant protein. In one embodiment of the method, the Ras superfamily protein is a KRras G12C mutant protein. In one embodiment of the method, the Ras superfamily protein is a KRras wild-type protein. In one embodiment of the method, the Ras superfamily protein is a KRras Q61H mutant protein. In one embodiment of the method, the Ras superfamily protein is a KRras G12D / Q61H double mutant protein. In one embodiment of the method, the Ras superfamily protein is a G12C / Q61H double mutant.

[0195] In one embodiment of the method, one or more members of the Ras superfamily are Rho. In one embodiment of the method, Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3; CDC42, or a variant thereof. In one embodiment of the method, the Ras superfamily protein is Rho-A protein.

[0196] In one embodiment of the method, one or more members of the Ras superfamily are Rac. In one embodiment of the method, Rho is Rac or a mutant thereof. In one embodiment of the method, Rac is RAC1; RAC2; RAC3; RHOG, or a mutant thereof. In one embodiment of the method, the Ras superfamily protein is Rac-1 protein.

[0197] In one embodiment of the method, the tagged protein is His-tagged. In one embodiment of the method, the ligand is nickel. In one embodiment of the method, the labeled GTP is Cy3-GTP or Cy5-GTP. In one embodiment of the method, the buffer is Buffer-I containing 50 mM Tris (pH 7.5), 150 mM NaCl, 1 mM MgCl2, and 1 mM DTT. In another embodiment of the method, the buffer is Buffer-I containing 50 mM Tris (pH 7.5), 1 mM MgCl2, and 1 mM DTT.

[0198] The assay format involves nickel-coated plates and binding of His-tagged proteins to native GTP that has been covalently labeled with a Cy3 or Cy5 fluorescent probe.

[0199] In theory, the assay is suitable for use with any GTP- or GDP-binding protein, and the examples demonstrate that the assay can be utilized with Ras and Ras mutants, Rac-1, and Rho-A human proteins expressed and purified as recombinant proteins.

[0200] A variety of tag / ligand combinations can be used in the assay. Proteins can be expressed as fusion proteins with tags such as His, HA, Flag, or GST; or proteins can be labeled with tags such as biotin via chemical reactions. A counter molecule (ligand or binder) that interacts with the tag is attached to or coated on a solid phase. The solid phase can be a plate (96-, 384-, or 1536-well plate) or a column bead such as sepharose, agarose, or cellulose. Binders can include nickel, antibodies, glutathione, and streptavidin. Examples of tag:ligand combinations include His (polyhistidine, at least six histidines):nickel, GST (glutathione-S-transferase):glutathione, HA (amino acids 98-106 of human influenza hemagglutinin):anti-HA antibody, Fc (constant region of human IgG):protein A, FLAG (peptide DYDDDDK):antibody (M1.M2, 4E11), Myc (myc protein derived from peptide EQKLISEED):anti-myc antibody, and biotin:streptavidin (or avidin).

[0201] Previous attempts to measure small molecule competitors for GTP-protein interactions have relied on the ability of the tested small molecule to prevent the binding of labeled GTP to the GTP-binding protein. A novel component of this assay is the use of highly sensitive Cy3 or Cy5 probes. Similar probes that can be used include other highly sensitive fluorophores and radioactive labels that can be detected at concentrations below 1 micromolar in solution. The inventors are unaware of any publications suggesting the adaptation of the probes we have used, or similar probes, for use in competitive binding assays.

[0202] Identification of amino acids in the GTP-binding domain of Ras that enable the development and function of small molecule targeted therapeutics As described above, it has also been discovered that amino acids in the GTP-binding domain of Ras, including Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147, and Mg202, enable previously unexpected competitive binding between compounds, such as small molecules, and GTP to that domain. It has also been discovered that amino acids in the GTP-binding domain of Ras, including Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147, and Mg202, enable previously unexpected competitive binding between compounds, such as small molecules, and GTP to that domain.

[0203] As described in Example 1, molecular modeling studies incorporating structures of Ras superfamily proteins from the RCSB PDB (www.rcsb.org) with GDP, the GTP analog GNP (guanosine 5'-[β,γ-imido]triphosphate trisodium salt hydrate), or a small molecule disclosed herein were used to determine the amino acids in the domain of the Ras superfamily that are in proximity to GDP, GTP, or the small molecule when bound to the Ras superfamily protein.

[0204] As described above, it has also been discovered that amino acids in the GTP-binding domain of Rac1, including Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, and Mg202, enable previously unexpected competitive binding between compounds, such as small molecules, and GTP to that domain.

[0205] As described above, it has also been discovered that amino acids in the GTP-binding domain of RhoA, including Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, and Mg202, enable previously unexpected competitive binding between compounds, such as small molecules, and GTP to that domain.

[0206] 5.3. Treatment method 5.3.1 Cancer In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that inhibits the function of one or more members of the Ras superfamily by binding to the GTP-binding domain or one or more members of the Ras superfamily. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that inhibits the function of Ras by binding to the GTP-binding domain of Ras. In another ... with an IC of less than 10 μM. 50 and K<10 μM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 1 μM. 50 and K<1 μM dProvided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 500 nM. 50 and K<500 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 470 nM. 50 and K less than 470 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 270 nM. 50 and K less than 270 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC50 of less than 200 nM. 50 and K<200 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC50 of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC50 of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 25% inhibition at 20 μM. Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 50% inhibition at 20 μM. Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 75% inhibition at 20 μM. Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 80% inhibition at 20 μM. Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 85% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 90% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 95% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 99% inhibition at 20 μM. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that inhibits the function of Rho by binding to the GTP-binding domain of Rho. In another embodiment, the method comprises ... 50 and K<10 μM dProvided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 1 μM. 50 and K<1 μM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC50 of less than 500 nM. 50 and K<500 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 270 nM. 50 and K less than 270 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC50 of less than 200 nM. 50 and K<200 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 130 nM. 50 and K less than 130 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC50 of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 25% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 50% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 75% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 80% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 85% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 90% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 95% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 99% inhibition at 20 μM. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that inhibits the function of Rac by binding to the GTP-binding domain of Rac. In another embodiment, the method comprises ... 50 and K<10 μM dProvided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 1 μM. 50 and K<1 μM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 500 nM. 50 and K<500 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 270 nM. 50 and K less than 270 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 200 nM. 50 and K<200 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 170 nM. 50 and K less than 170 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC50 of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 25% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 50% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 75% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 80% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 85% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 90% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 95% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing cancer, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 99% inhibition at 20 μM.

[0207] In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to four or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to five or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to seven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to eight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to ten or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 11 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 12 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 14 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 15 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 16 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 17 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 18 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 19 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 20 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 21 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 22 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 23 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.

[0208] In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to four or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to five or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to seven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to eight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to ten or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 11 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 12 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 14 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 15 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 16 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 17 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 18 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 19 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 20 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 21 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 22 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 23 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.

[0209] In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In another embodiment, the Ras is HRAS, KRAS, or NRAS. In one embodiment, the Ras is HRAS. In one embodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. In another embodiment, the Ras is a mutant form of Ras described herein.

[0210] In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to two or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to three or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to four or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to five or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to six or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to seven or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to eight or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to nine or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 10 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 11 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 12 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 13 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 14 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 15 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 16 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 17 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to all of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.

[0211] In one embodiment, Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3 or CDC42. In one embodiment, Rho is RHOA. In another embodiment, Rho is a mutant form of Rho described herein.

[0212] In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to two or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the highly conserved GTP-binding domain of Rho. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to three or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to four or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to five or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to six or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to seven or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to eight or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to nine or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 10 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to eleven or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 12 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 13 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 14 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 15 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 16 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 17 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to 18 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing cancer, the method comprising administering to a subject a compound that binds to all of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.

[0213] In one embodiment, Rho is Rac. In one embodiment, Rac is RAC1; RAC2; RAC3 or RHOG. In one embodiment, Rac is RAC1. In another embodiment, Rac is a mutant form of Rac described herein.

[0214] In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to one or more members of the Ras superfamily. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Ras. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Rho. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Rac. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Ras and Rho. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Ras and Rac. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Rho and Rac. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Ras, Rho, and Rac. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 2000 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1750 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1500 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1250 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1000 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 750 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 665 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 500 daltons. In another embodiment, the compounds used in the methods and compositions provided herein contain an oxadiazole, thiadiazole, or triazole moiety.In another embodiment, the compound used in the methods and compositions provided herein contains a 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole moiety, 2-acylaminothiazole, 2-(pyridin-2-yl)pyrimidin-4-amine, 2-(pyridin-2-yl)pyrimidin-4-ol, 2-(pyridin-2-yl)pyrimidin-4-(1H)-one, 2-(pyridin-2-yl)pyrimidin-4(3H)-one, 2-(pyridin-2-yl)pyrimidin-4(1H)-imine, or 2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety. In another embodiment, the compound used in the methods and compositions provided herein is 2-(pyridin-2-yl)pyrimidin-4-amine, 2-(pyridin-2-yl)pyrimidin-4-ol, 2-(pyridin-2-yl)pyrimidin-4-(1H)-one, 2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one, 2-(imidazol-2-yl)pyrimidin-4(1H)-one, 2-(imidazol-2-yl)pyrimidin-4-amine, 2-(imidazole 2-(imidazol-4-yl)pyrimidin-4(3H)-imine, 2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol, 2-(imidazol-4-yl)pyrimidin-4(3H)-one, 2-(imidazol-4-yl)pyrimidin-4(1H)-one, 2-(imidazol-4-yl)pyrimidin-4-amine, 2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or 2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety.

[0215] In one embodiment, provided herein is a method of treating or preventing cancer, the method comprising administering to a subject a compound provided herein, or a derivative thereof.

[0216] In another embodiment, provided herein is a method for managing cancer, comprising administering to a subject a compound provided herein, or a derivative thereof.

[0217] Also provided herein are methods for treating subjects who have previously been treated for cancer but are unresponsive to standard therapy, as well as for subjects who have not received prior treatment. Also provided are methods for treating subjects regardless of their age, although some diseases or disorders are more prevalent in certain age groups. Also provided are methods for treating subjects who have undergone surgery in an attempt to treat the disease or condition in question, as well as subjects who have not. Because subjects with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a subject may vary depending on their prognosis. A skilled clinician can easily determine, without undue experimentation, the specific secondary agents, types of surgery, and types of non-drug-based standard therapy that can be effectively used to treat an individual subject with cancer.

[0218] As used herein, the term "cancer" includes, but is not limited to, solid tumors and blood-borne tumors. The term "cancer" refers to diseases of the skin tissue, organs, blood, and blood vessels, including, but not limited to, cancer of the bladder, bone, blood, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovary, pancreas, prostate, rectum, stomach, testicles, throat, and uterus. Specific cancers include: advanced malignant tumors, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brainstem glioma, poor prognosis malignant brain tumors, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumors, rectal adenocarcinoma, Dukes C and D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karyotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, low-grade follicular lymphoma, malignant melanoma, malignant mesothelioma, and malignant pleural effusion. These include, but are not limited to, mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecological sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube carcinoma, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma.

[0219] In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is metastatic. In some embodiments, the solid tumor is drug-resistant. In some embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrial cancer, skin cancer (melanoma), cervical cancer, urinary tract cancer, or glioblastoma.

[0220] In some embodiments, the cancer is a blood-borne tumor. In some embodiments, the blood-borne tumor is metastatic. In some embodiments, the blood-borne tumor is drug-resistant. In some embodiments, the cancer is leukemia.

[0221] In one embodiment, the methods provided herein encompass treating, preventing, or managing various types of leukemia, such as chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute myeloblastic leukemia (AML), by administering a therapeutically effective amount of a compound provided herein or a derivative thereof.

[0222] In some embodiments, the methods provided herein encompass treating, preventing, or managing acute leukemia in a subject. In some embodiments, the acute leukemia is acute myeloid leukemia (AML), including, but not limited to, anaplastic AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyeloblastic leukemia (M3 or M3 variant (M3V)), myelomonocytic leukemia (M4 or M4 variant with eosinophilia (M4E)), monocytic leukemia (M5), erythroleukemia (M6), and megakaryoblastic leukemia (M7). In one embodiment, the acute myeloid leukemia is anaplastic AML (M0). In one embodiment, the acute myeloid leukemia is myeloblastic leukemia (M1). In one embodiment, the acute myeloid leukemia is myeloblastic leukemia (M2). In one embodiment, the acute myeloid leukemia is promyeloblastic leukemia (M3 or M3 variant (M3V)). In one embodiment, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia (M4E)). In one embodiment, the acute myeloid leukemia is monocytic leukemia (M5). In one embodiment, the acute myeloid leukemia is erythroleukemia (M6). In one embodiment, the acute myeloid leukemia is megakaryoblastic leukemia (M7). Thus, a method of treating, preventing, or managing acute myeloid leukemia in a subject comprises administering to the subject a compound provided herein or a derivative thereof, alone or in combination, in an amount effective to treat, prevent, or manage acute myeloid leukemia. In some embodiments, the method comprises administering to the subject a compound provided herein or a derivative thereof in combination with a second active agent in an amount effective to treat, prevent, or manage acute myeloid leukemia.

[0223] In some embodiments, the methods provided herein encompass treating, preventing, or managing acute lymphocytic leukemia (ALL) in a subject. In some embodiments, acute lymphocytic leukemia includes leukemia originating from blast cells (B cells) in the bone marrow, the thymus (T cells), and lymph nodes. Acute lymphocytic leukemia can be classified according to the French-American-British (FAB) morphological classification scheme as follows: L1 - mature appearing lymphoblasts (T cells or pre-B cells), L2 - immature and pleomorphic (variously shaped) lymphoblasts (T cells or pre-B cells), and L3 - lymphoblasts (B cells; Burkitt cells). In one embodiment, acute lymphocytic leukemia originates from blast cells (B cells) in the bone marrow. In one embodiment, acute lymphocytic leukemia originates from the thymus (T cells). In one embodiment, acute lymphocytic leukemia originates from lymph nodes. In one embodiment, the acute lymphocytic leukemia is an L1 type characterized by mature appearing lymphoblasts (T cells or pre-B cells). In one embodiment, the acute lymphocytic leukemia is an L2 type characterized by immature and pleomorphic (variously shaped) lymphoblasts (T cells or pre-B cells). In one embodiment, the acute lymphocytic leukemia is an L3 type characterized by lymphoblasts (B cells; Burkitt cells). In certain embodiments, the acute lymphocytic leukemia is a T-cell leukemia. In one embodiment, the T-cell leukemia is peripheral T-cell leukemia. In another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In another embodiment, the T-cell leukemia is cutaneous T-cell leukemia. In another embodiment, the T-cell leukemia is adult T-cell leukemia. Thus, a method for treating, preventing, or managing acute lymphocytic leukemia in a subject includes administering to the subject a compound provided herein or a derivative thereof, alone or in combination with a second active agent, in an amount effective to treat, prevent, or manage acute lymphocytic leukemia. In some embodiments, the method includes administering to the subject a compound provided herein or a derivative thereof, in combination with a second active agent, in an amount effective to treat, prevent, or manage acute lymphocytic leukemia.

[0224] In some embodiments, the methods provided herein include treating, preventing, or managing chronic myeloid leukemia (CML) in a subject. The methods include administering to the subject a compound provided herein, or a derivative thereof, in an amount effective to treat, prevent, or manage chronic myeloid leukemia. In some embodiments, the methods include administering to the subject a compound provided herein, or a derivative thereof, in combination with a second active agent in an amount effective to treat, prevent, or manage chronic myeloid leukemia.

[0225] In some embodiments, the methods provided herein include treating, preventing, or managing chronic lymphocytic leukemia (CLL) in a subject. The methods include administering to the subject a compound provided herein, or a derivative thereof, in an amount effective to treat, prevent, or manage chronic lymphocytic leukemia. In some embodiments, the methods include administering to the subject a compound provided herein, or a derivative thereof, in combination with a second active agent in an amount effective to treat, prevent, or manage chronic lymphocytic leukemia.

[0226] In certain embodiments, provided herein are methods of treating, preventing, and / or managing disease in a subject with impaired renal function. In certain embodiments, provided herein are methods of treating, preventing, and / or managing cancer in a subject with impaired renal function. In certain embodiments, provided herein are methods of providing appropriate dose adjustments for a subject with impaired renal function due to, but not limited to, disease, aging, or other subject factors.

[0227] In certain embodiments, provided herein are methods for treating, preventing, and / or managing lymphoma, including non-Hodgkin's lymphoma. In some embodiments, provided herein are methods for the treatment or management of non-Hodgkin's lymphoma (NHL), including but not limited to, diffuse large B-cell lymphoma (DLBCL), using prognostic factors.

[0228] In certain embodiments, provided herein are methods for treating, preventing, and / or managing multiple myeloma, including relapsed / refractory multiple myeloma, in a subject with renal impairment or symptoms thereof, comprising administering a therapeutically effective amount of a compound provided herein, or a derivative thereof, to a subject with relapsed / refractory multiple myeloma and renal impairment.

[0229] In certain embodiments, the therapeutically or prophylactically effective amount of the compound is about 0.005 to about 1,000 mg per day, about 0.01 to about 500 mg per day, about 0.01 to about 250 mg per day, about 0.01 to about 100 mg per day, about 0.1 to about 100 mg per day, about 0.5 to about 100 mg per day, about 1 to about 100 mg per day, about 0.01 to about 50 mg per day, about 0.1 to about 50 mg per day, about 0.5 to about 50 mg per day, about 1 to about 50 mg per day, about 0.02 to about 25 mg per day, about 0.05 to about 10 mg per day, about 0.05 to about 5 mg per day, about 0.1 to about 5 mg per day, or about 0.5 to about 5 mg per day.

[0230] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.

[0231] In one embodiment, the recommended daily dose range for the compounds provided herein, or derivatives thereof, for the conditions described herein is in the range of about 0.5 mg to about 50 mg per day, in one embodiment given as a single dose once daily or in divided doses throughout the day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 mg to about 5 mg per day. Specific daily doses include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

[0232] In specific embodiments, the recommended starting dosage may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, or 50 mg per day. In other embodiments, the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose may be increased to 15, 20, 25, 30, 35, 40, 45, and 50 mg per day. In specific embodiments, the compound may be administered in an amount of about 25 mg per day. In certain embodiments, the compound may be administered in an amount of about 10 mg per day. In certain embodiments, the compound may be administered in an amount of about 5 mg per day. In certain embodiments, the compound may be administered in an amount of about 4 mg per day. In certain embodiments, the compound may be administered in an amount of about 3 mg per day.

[0233] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.001 to about 100 mg / kg / day, about 0.01 to about 50 mg / kg / day, about 0.01 to about 25 mg / kg / day, about 0.01 to about 10 mg / kg / day, about 0.01 to about 9 mg / kg / day, 0.01 to about 8 mg / kg / day, about 0.01 to about 7 mg / kg / day, about 0.01 to about 6 mg / kg / day, about 0.01 to about 5 mg / kg / day, about 0.01 to about 4 mg / kg / day, about 0.01 to about 3 mg / kg / day, about 0.01 to about 2 mg / kg / day, about 0.01 to about 1 mg / kg / day, or about 0.01 to about 0.05 mg / kg / day.

[0234] The administered dose may also be expressed in units other than mg / kg / day. For example, parenteral doses may be expressed in mg / m 2 The skilled artisan will take into account either the height or weight of the subject, or both, to determine the dosage from mg / kg / day to mg / m 2 It will be easy to see how this is converted to a dose of 38 mg / m² / day (see www.fda.gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / kg / day for a 65 kg human is 38 mg / m². 2 Approximately equal to / day.

[0235] In certain embodiments, the amount of compound administered is sufficient to provide a steady-state plasma concentration of the compound in the range of about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, about 1 to about 50 μM, about 0.02 to about 25 μM, about 0.05 to about 20 μM, about 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM.

[0236] In other embodiments, the amount of compound administered is sufficient to provide a steady-state plasma concentration of the compound in the range of about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM, or about 50 to about 100 nM.

[0237] As used herein, the term "steady-state plasma concentration" refers to the concentration reached after a period of administration of a compound provided herein, or a derivative thereof. When steady state is reached, there are small peaks and troughs in the time-dependent curve of the plasma concentration of the compound.

[0238] In certain embodiments, the amount of compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound in the range of about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, about 1 to about 50 μM, about 0.02 to about 25 μM, about 0.05 to about 20 μM, about 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM.

[0239] In certain embodiments, the amount of compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound in the range of about 0.001 to about 500 μM, about 0.002 to about 200 μM, about 0.005 to about 100 μM, about 0.01 to about 50 μM, about 1 to about 50 μM, about 0.01 to about 25 μM, about 0.01 to about 20 μM, about 0.02 to about 20 μM, about 0.02 to about 20 μM, or about 0.01 to about 20 μM.

[0240] In certain embodiments, the amount of compound administered is from about 100 to about 100,000 ng. * hour / mL, approximately 1,000~50,000ng * hour / mL, approximately 5,000 to approximately 25,000ng * h / mL, or approximately 5,000 to 10,000 ng * It is sufficient to provide the area under the curve (AUC) of the compound in the range of 1000 mg / mL.

[0241] In some embodiments, the subject treated with one of the methods provided herein has not been treated with an anti-cancer therapy before administering the compound provided herein or a derivative thereof. In some embodiments, the subject treated with one of the methods provided herein has been treated with an anti-cancer therapy before administering the compound provided herein or a derivative thereof. In some embodiments, the subject treated with one of the methods provided herein has developed drug resistance to the anti-cancer therapy.

[0242] The methods provided herein encompass treating patients regardless of the subject's age, although some diseases or disorders are more prevalent in certain age groups.

[0243] Depending on the disease to be treated and the condition of the subject, the compounds provided herein, or derivatives thereof, can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compounds provided herein, or derivatives thereof, can be formulated in suitable dosage units, alone or together with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each administration route.

[0244] In one embodiment, the compounds provided herein, or derivatives thereof, are administered orally. In another embodiment, the compounds provided herein, or derivatives thereof, are administered parenterally. In yet another embodiment, the compounds provided herein, or derivatives thereof, are administered intravenously.

[0245] The compounds provided herein, or derivatives thereof, can be delivered as a single dose, e.g., a single bolus injection, or oral tablets or pills; or over time, e.g., by continuous infusion over time or divided bolus doses over time. The compounds can be administered repeatedly as needed, e.g., until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. For example, stable disease in the case of solid tumors generally means that the perpendicular diameter of a measurable lesion has not increased by more than 25% since the last measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3):205-216 (2000). Stable disease, or lack thereof, is determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination, visualization of the tumor using X-ray, CAT, PET, or MRI scans, and other commonly accepted evaluation modalities.

[0246] The compounds provided herein, or derivatives thereof, can be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID), three times daily (TID), and four times daily (QID). Administration can also be continuous (i.e., every other day on consecutive days or every day), intermittent, e.g., cyclic (i.e., with a drug-free rest period of several days, weeks, or months). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as a compound provided herein, or a derivative thereof, is administered, for example, once or more times each day for a period of time. The term "continuous" is intended to mean that a therapeutic compound, such as a compound provided herein, or a derivative thereof, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The terms "intermittent" or "intermittently," as used herein, are intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of a compound provided herein or a derivative thereof can be administration for 1-6 days per week, administration in cycles (e.g., daily administration for 2-8 consecutive weeks followed by a rest period of up to 1 week without administration), or administration every other day. The term "cycle," as used herein, is intended to mean that a therapeutic compound, such as a compound provided herein or a derivative thereof, is administered daily or continuously, but with a rest period. In some such embodiments, administration is once daily for 2-6 days, followed by a rest period of 5-7 days without administration.

[0247] In some embodiments, the frequency of administration ranges from approximately daily dosing to approximately monthly dosing. In certain embodiments, administration is once daily, twice daily, three times daily, four times daily, once every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compounds provided herein, or derivatives thereof, are administered once daily. In another embodiment, the compounds provided herein, or derivatives thereof, are administered twice daily. In yet another embodiment, the compounds provided herein, or derivatives thereof, are administered three times daily. In yet another embodiment, the compounds provided herein, or derivatives thereof, are administered four times daily.

[0248] In certain embodiments, a compound provided herein, or a derivative thereof, is administered once daily for 1 day to 6 months, 1 week to 3 months, 1 week to 4 weeks, 1 week to 3 weeks, or 1 week to 2 weeks. In certain embodiments, a compound provided herein, or a derivative thereof, is administered once daily for 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, a compound provided herein, or a derivative thereof, is administered once daily for 4 days. In one embodiment, a compound provided herein, or a derivative thereof, is administered once daily for 5 days. In one embodiment, a compound provided herein, or a derivative thereof, is administered once daily for 6 days. In one embodiment, a compound provided herein, or a derivative thereof, is administered once daily for 1 week. In another embodiment, a compound provided herein, or a derivative thereof, is administered once daily for 2 weeks. In yet another embodiment, a compound provided herein, or a derivative thereof, is administered once daily for 3 weeks. In yet another embodiment, a compound provided herein, or a derivative thereof, is administered once daily for 4 weeks.

[0249] Combination therapy with a second active agent The compounds provided herein, or derivatives thereof, may also be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of cancer as described herein.

[0250] In one embodiment, provided herein is a method of treating, preventing, or managing cancer, comprising administering to a subject a compound provided herein, or a derivative thereof, in combination with one or more second active agents, and optionally in combination with radiation therapy, blood transfusion, or surgery. Examples of second active agents are disclosed herein.

[0251] As used herein, the term "in combination" includes the use of more than one therapies (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disease or disorder. The first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided herein, a compound provided herein, or a derivative thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.

[0252] The administration of a compound provided herein, or a derivative thereof, and one or more second active agents to a subject can be simultaneous or sequential, by the same or different administration routes. The suitability of a particular administration route for a particular active agent depends on the active agent itself (e.g., whether it can be administered orally without being degraded before entering the bloodstream) and the cancer being treated.

[0253] The route of administration of the compound provided herein, or a derivative thereof, is independent of the route of administration of the second therapy. In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously. Thus, according to these embodiments, the compound provided herein, or a derivative thereof, is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, bucally, intranasally, liposomally, by inhalation, vaginally, intraocularly, by local delivery via a catheter or stent, subcutaneously, intraadiposely, intraarticularly, intrathecally, or in a delayed-release dosage form. In one embodiment, the compound provided herein, or a derivative thereof, and the second therapy are administered by the same administration mode, either orally or by IV. In another embodiment, a compound provided herein, or a derivative thereof, is administered by one mode of administration, e.g., IV, while the second agent (anticancer agent) is administered by another mode of administration, e.g., orally.

[0254] In one embodiment, the second active agent is administered intravenously or subcutaneously in an amount of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg once or twice daily. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of the disease, and the amount of a compound provided herein, or derivative thereof, as well as any additional active agents co-administered to the subject.

[0255] In the methods and compositions provided herein, one or more second active ingredients or agents can be used in conjunction with the compounds provided herein, or derivatives thereof. The second active agent can be a large molecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic, or organic molecule).

[0256] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, particularly therapeutic antibodies against cancer antigens. Typical large molecule active agents are biomolecules such as naturally occurring, synthetic, or recombinant proteins. Proteins particularly useful in the methods and compositions provided herein include proteins that stimulate the survival and / or proliferation of hematopoietic progenitor cells and immunologically active neoplastic cells in vitro or in vivo. Other useful proteins stimulate the division and differentiation of committed erythroid progenitor cells within cells in vitro or in vivo. Specific proteins include, but are not limited to, interleukins such as IL-2 (including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-18; interferons such as interferon alpha-2a, interferon alpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-Ia, and interferon gamma-Ib; GM-CF and GM-CSF; and EPO.

[0257] In certain embodiments, GM-CSF, G-CSF, SCF, or EPO is administered at a dose of about 1 to about 750 mg / m 2 / day, about 25~500mg / m 2 / day, about 50~250mg / m 2 / day, or about 50 to about 200 mg / m 2 In certain embodiments, GM-CSF is administered subcutaneously over two hours in an amount ranging from about 60 to about 500 mcg / m 2 / day for about five days in a four or six week cycle. 2 or subcutaneously about 5 to about 12 mcg / m 2 In certain embodiments, G-CSF may be administered subcutaneously in an amount of about 1 mcg / kg / day initially and adjusted depending on the rise in total granulocyte count. A maintenance dose of G-CSF may be administered subcutaneously in an amount of about 300 (in smaller subjects) or 480 mcg. In certain embodiments, EPO may be administered subcutaneously in an amount of 10,000 units three times a week.

[0258] Specific proteins that may be used in the methods and compositions include, but are not limited to, filgrastim, sold in the United States under the trade name Neupogen® (Amgen, Thousand Oaks, CA); sargramostim, sold in the United States under the trade name Leukine® (Immunex, Seattle, WA); and recombinant EPO, sold in the United States under the trade name Epogen® (Amgen, Thousand Oaks, CA).

[0259] Recombinant and mutant forms of GM-CSF can be prepared as described in U.S. Patent Nos. 5,391,485; 5,393,870; and 5,229,496, all of which are incorporated herein by reference. Recombinant and mutant forms of G-CSF can be prepared as described in U.S. Patent Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755, all of which are incorporated herein by reference in their entireties.

[0260] Native, naturally occurring, and recombinant proteins are also provided for use in combination with the compounds provided herein, or derivatives thereof. Additionally, mutants and derivatives (e.g., modified forms) of naturally occurring proteins are included that exhibit at least some of the pharmacological activity of the protein on which they are based in vivo. Examples of mutants include, but are not limited to, proteins with one or more amino acid residues that differ from the corresponding residues in the naturally occurring form of the protein. The term "mutant" also includes proteins that lack carbohydrate moieties normally present in their naturally occurring form (e.g., non-glycosylated forms). Examples of derivatives include, but are not limited to, pegylated derivatives and fusion proteins, such as proteins formed by fusing IgG1 or IgG3 to the protein or active portion of the protein of interest. See, e.g., Penichet, M.L., and Morrison, S.L., J. Immunol. Methods 248:91-101 (2001).

[0261] Antibodies that can be used in combination with the compounds provided herein, or derivatives thereof, include monoclonal and polyclonal antibodies. Examples of antibodies include, but are not limited to, trastuzumab (Herceptin®), rituximab (Rituxan®), bevacizumab (Avastin™), pertuzumab (Omnitarg™), tositumomab (Bexar®), edrecolomab (Panorex®), and G250. The compounds provided herein, or their enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, clathrates, or polymorphs thereof, can also be combined or used in combination with anti-TNF-α antibodies and / or anti-EGFR antibodies, such as Erbitux® or panitumumab.

[0262] Large molecule active agents can be administered in the form of anti-cancer vaccines. For example, vaccines that secrete or induce the secretion of cytokines such as IL-2, G-CSF, and GM-CSF can be used in the provided methods and pharmaceutical compositions. See, e.g., Emens, LA, et al., Curr. Opinion Mol. Ther. 3(1):77-84 (2001).

[0263] Small molecule second active agents can also be used to reduce adverse effects associated with the administration of the compounds provided herein or derivatives thereof. However, like some large molecules, many are believed to be able to provide synergistic effects when administered together with the compounds provided herein or derivatives thereof (e.g., before, after, or simultaneously). Examples of small molecule second active agents include, but are not limited to, anticancer drugs, antibiotics, immunosuppressants, and steroids.

[0264] In certain embodiments, the second agent is an HSP inhibitor, a proteasome inhibitor, a FLT3 inhibitor, or a TOR kinase inhibitor.

[0265] Examples of anti-cancer agents used in the methods or compositions described herein include acivicin; aclarubicin; acodazole hydrochloride; acronine; adzelesin; aldesleukin; altretamine; ambomycin; amethanthrone acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacytidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; visnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan Antihistamine; Cactinomycin; Calsterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin hydrochloride; Carzelesin; Cedefingol; Celecoxib (COX-2 inhibitor); Chlorambucil; Cilolemycin; Cisplatin; Cladribine; Clofarabine; Crisnatol mesilate; Cyclophosphamide; Ara-C; Dacarbazine; Dactinomycin; Daunorubicin hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine mesilate; Diazicon; Docetaxel; Doxorubicin; Doxorubicin hydrochloride Salt;Droloxifene;Droloxifene citrate;Dromostanolone propionate;Duazomycin;Edatrexate;Eflornithine hydrochloride;Elsamitrucin;Enloplatin;Enpromate;Epipropizine;Epirubicin hydrochloride;Elburozole;Esorubicin hydrochloride;Estramustine;Estramustine sodium phosphate;Etanidazole;Etoposide;Etoposide phosphate;Etoprine;Fadrozole hydrochloride;Fazarabine;Fenretinide;Floxuridine;Fludarabine phosphate;Fluorouracil;Furocitabine ;Fosquidone;Fostriesin sodium;Gemcitabine;Gemcitabine hydrochloride;Hydroxyurea;Idarubicin hydrochloride;Ifosfamide;Irmofosine;Iproplatin;Irinotecan;Irinotecan hydrochloride;Lanreotide acetate;Letrozole;Leuprolide acetate;Liarozole hydrochloride;Lometrexol sodium;Lomustine;Losoxantrone hydrochloride;Masoprocol;Maytansine;Mechlorethamine hydrochloride;Megestrol acetate;Melengestrol acetate;Melphalan;Menogaril;Mercaptopurine;Methotrexate;Methotrexate sodium; Metoprine; Meturedepa; Mitindomide; Mitocalcin; Mitochromin; Mitogillin; Mitomarcin; Mitomycin; Mitospar; Mitotane; Mitoxantrone hydrochloride; Mycophenolic acid; Nocodazole; Nogalamycin; Omacetaxine; Omaplatin; Oxisuran; Paclitaxel; Pegaspargase; Periomycin; Pentamustine; Peplomycin sulfate; Perfosfamide; Pipobro Man; Piposulfan; Piroxantrone hydrochloride; Plicamycin; Promestane; Porfimer sodium; Porfiromycin; Prednimustine; Procarbazine hydrochloride; Puromycin; Puromycin hydrochloride; Pirazofurin; Ribopurin; Safingol; Safingol hydrochloride; Semustine; Simtrazene; Sorafenib; Sparfosate sodium; Sparsomycin; Spirogermanium hydrochloride; Spiromustine; S Piroplatin;Streptonigrin;Streptozocin;Sulofenur;Tallysomycin;Tecogalan sodium;Taxotere;Tegafur;Teroxantrone hydrochloride;Temoporfin;Teniposide;Teroxylon;Testolactone;Thiamiprine;Thioguanine;Thiotepa;Tiazofurin;Tirapazamine;Toremifene citrate;Trestron acetate;Triciribine phosphate;Trimetrexate;Trimetrexate glucuronide salt; triptorelin; tubrozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglisinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrocidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0266] Other anti-cancer drugs that can be included in the methods or compositions include 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecipenol; adzelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal morphogenetic protein-1; antiandrogens, Prostate cancer;Antiestrogens;Antineoplastic agents;Antisense oligonucleotides;Aphidicolin glycinate;Apoptotic gene modulators;Apoptosis control agents;Apurinic acid;ara-CDP-DL-PTBA;Arginine deaminase;Asulaculin;Atamestane;Atlimustine;Axinastatin 1;Axinastatin 2;Axinastatin 3;Azasetron;Azatoxins;Azatyrosine;Baccatin III derivatives;Balanol;Batimastat;BCR / ABL antagonists;Benzochlorins;Benzoylstaurosporines;Beta-lactam derivatives ;Beta-alletin;Betaclamycin B;Betulinic acid;bFGF inhibitors;Bicalutamide;Bisantrene;Bisaziridinylspermine;Bisnafide;Bistraten A;Bizelesin;Brefurate;Bropirimine;Budotitanium;Buthionine sulfoximine;Calcipotriol;Calphostin C;Camptothecin derivatives;Capecitabine;Carboxamido-amino-triazoles;Carboxamidotriazoles;CaRestM3;CARN700;Cartilage-derived inhibitors;Carzelesin;Casein kinase inhibitors (ICOS);Castanospermine;Securo Pin B; Cetrorelix; Chloruron; Chloroquinoxaline sulfonamides; Cicaprost; Cisporphyrins; Cladribine; Clomiphene analogs; Clotrimazole; Collismycin A; Collismycin B; Combretastatin A4; Combretastatin analogs; Conagenin; Crambesidin 816; Crisnatol; Cryptophycin 8; Cryptophycin A derivatives; Curacin A; Cyclopentanthraquinone; Cycloplatam; Sipemycin; Ara-C-ocfosphate; Cytolytic factors; Cytostatin; Dacliximab; Decitabine;Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexphosphamide; Dexrazoxane; Dexverapamil; Diazicon; Didemnin B; Didox; Diethylnorspermine; Dihydro-5-azacytidine; Dihydrotaxol, 9-; Dioxamycin; Diphenylspiromustine; Docetaxel; Docosanol; Dolasetron; Doxifluridine; Doxorubicin; Droloxifene; Dronabinol; Duocarmycin SA; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Eflornithine; Elemene; Emitef Epirubicin; Epristeride; Estramustine analogs; Estrogen agonists; Estrogen antagonists; Etanidazole; Etoposide phosphate; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Flezelastine; Fluasterone; Fludarabine; Fluorodaunornithine hydrochloride; Forfenimex; Formestane; Fostriecin; Fotemustine; Gadolinium texaphyrin; Gallium nitrate; Galocitabine; Ganirelix; Gelatinase inhibitors; Gemcitabine Glutathione inhibitors; Hepsulfam; Heregulin; Hexamethylene bisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idramanton; Ilmofosine; Ilomastat; Imatinib (e.g., Gleevec®); Imiquimod; Immunostimulating peptides; Insulin-like growth factor-1 receptor inhibitors; Interferon agonists; Interferons; Interleukins; Iobenguane; Iododoxorubicin; Ipomeanol, 4-; Ilopract; Irsogladine; Isobengazole; Isohomohalichondrin B ;Itasetron;Jasplakinolide;Kahalide F;Lamellarin-N triacetate;Lanreotide;Leinamycin;Lenograstim;Lentinan sulfate;Leptolstatin;Letrozole;Leukemia inhibitory factor;Leukocyte alpha interferon;Leuprolide + estrogen + progesterone;Leuprorelin;Levamisole;Liarozole;Linear polyamine analogues;Lipophilic disaccharide peptides;Lipophilic platinum compounds;Lysocrine amide 7;Lobacillus acidophilus;Lometrexol;Lonidamine;Losoxantrone;Loxoribine;Lurtotecan;Lutetium texaphyrin; lysofylline; lytic peptides; maytansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; mervalone; meterelin; methioninase; metoclopramide; MIF inhibitors; mifepristone; miltefosine; millimostim; mitoguazone; mitolactol; mitomycin analogs; mitonafide; mitotoxin fibroblast growth factor saporin; mitoxantrone; mofalotene; molgramostim; Erbitux, human Chorionic gonadotropin; monophosphoryl lipid A + mycobacterial cell wall SK; mopidamol; mustard anticancer drugs; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagressip; naloxone + pentazocine; napavine; nafterpine; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidants; nitrulline; oblimersen (Genasense®); O6 benzylguanine; O Treotide; Oxenon; Oligonucleotides; Onapristone; Ondansetron; Ondansetron; Oracin; Oral cytokine inducers; Ormaplatin; Osateron; Oxaliplatin; Oxaunomycin; Paclitaxel; Paclitaxel analogs; Paclitaxel derivatives; Palauamine; Palmitoylrhizoxin; Pamidronic acid; Panaxytriol; Panomyphen; Parabactin; Pazeliptin; Pegaspargase; Perdecin; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Pegaspargase Lylyl alcohol;Phenazinomycin;Phenyl acetate;Phosphatase inhibitors;Picibanil;Pilocarpine hydrochloride;Pirarubicin;Piritrexim;Prasetin A;Prasetin B;Plasminogen activator inhibitors;Platinum complexes;Platinum compounds;Platinum triamine complexes;Porfimer sodium;Porfiromycin;Prednisone;Propylbisacridone;Prostaglandin J2;Proteasome inhibitors;Protein A system immunomodulators;Protein kinase C inhibitors;Protein kinase C inhibitors, microalgae;Protein tyrosine phosphatase inhibitors;Purine nucleoside phosphorylase inhibitors; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethylene conjugates; RAF antagonists; Raltitrext; Ramosetron; Ras farnesyl protein transferase inhibitors; Ras inhibitors; Ras-GAP inhibitors; Demethylated leteriptin; Rhenium Re186 etidronate; Rhizoxin; Ribozyme; RII retinamide; Rohitucin; Romurtide; Roquinimex; Rubidinone B1; Ruboxil; Safingol; Saitopine; SarCNU; Sarcophytol A; sargramostim; Sdi1 mimetic; semustine; senescence-induced inhibitor 1; sense oligonucleotide; signal transduction inhibitor; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; sorberol; somatomedin-binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stipiamide; stromelysin inhibitor; sulfinosine; superactive vasoactive intestinal peptide antagonist; suragitan; suramin; swa Insonine; Talimustine; Tamoxifen methiodide; Tauromustine; Tazarotene; Tecogalan sodium; Tegafur; Terlapyrylium; Telomerase inhibitors; Temoporfin; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Saliblastine; Thiocoraline; Thrombopoietin; Thrombopoietin mimetics; Thymalfasin; Thymopoietin receptor agonists; Thymotrin; Thyroid-stimulating hormone; Tin ethyl etiopurpurin; Tirapazamine; Titanocene dichloride; Topsentin; Toremifene; Translation inhibitors; These include, but are not limited to, tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonists; vapreotide; variolin B; veraresol; veramine; verudine; verteporfin; vinorelbine; vinxartin; vitaxin; vorozole; zanoteron; zeniplatin; zilascorub; and zinostatin stimalamer.

[0267] Specific second active agents particularly useful in the methods or compositions include rituximab, oblimersen (Genasense®), Remicade, docetaxel, celecoxib, melphalan, dexamethasone (Decadron®), steroids, gemcitabine, cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, rifapril ... These include, but are not limited to, Xert, Alisa®, Taxol, Taxotere, fluorouracil, leucovorin, irinotecan, Xeloda, CPT-11, interferon alpha, pegylated interferon alpha (e.g., PEG Intron-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, Ara-C, doxetaxol, paclitaxel, vinblastine, IL-2, GM CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonates, arsenic trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate (Emsit®), sulindac, and etoposide.

[0268] In certain embodiments of the methods provided herein, the use of a second active agent in combination with a compound provided herein, or a derivative thereof, can be modified or delayed during or immediately after administration of the compound provided herein, or a derivative thereof, as deemed appropriate by one of skill in the art. In certain embodiments, a subject receiving a compound provided herein, or a derivative thereof, alone or in combination with other therapies, can receive supportive care, including antiemetics, bone marrow growth factors, and platelet transfusions, as needed. In some embodiments, a subject receiving a compound provided herein, or a derivative thereof, can be administered a growth factor as a second active agent, according to the judgment of one of skill in the art. In some embodiments, administration of a compound provided herein, or a derivative thereof, in combination with erythropoietin or darbepoietin (Aranesp) is provided.

[0269] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in conjunction with gemcitabine and cisplatinum to a subject with locally advanced or metastatic transitional cell bladder cancer.

[0270] In certain embodiments, the compounds provided herein, or derivatives thereof, are administered in combination with a second active ingredient, such as: temozolomide (for pediatric subjects with recurrent or progressive brain tumors or recurrent neuroblastoma); celecoxib, etoposide, and cyclophosphamide (for recurrent or progressive CNS cancers); temodar (for subjects with recurrent or progressive meningioma, malignant meningioma, hemangiopericytoma, multiple brain metastases, recurrent brain tumors, or newly diagnosed glioblastoma multiforme); irino Tecan (for subjects with recurrent glioblastoma); carboplatin (for pediatric subjects with brainstem glioma); procarbazine (for pediatric subjects with progressive malignant glioma); cyclophosphamide (for subjects with poor prognosis malignant brain tumors, newly diagnosed or recurrent glioblastoma multiforme); Gliadel® (for high-grade recurrent malignant glioma); temozolomide and tamoxifen (for anaplastic astrocytoma); or topotecan (for glioma, glioblastoma, anaplastic astrocytoma or anaplastic oligodendroglioma).

[0271] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with metastatic breast cancer in combination with methotrexate, cyclophosphamide, a taxane, abraxane, lapatinib, herceptin, an aromatase inhibitor, a selective estrogen modulator, an estrogen receptor antagonist, and / or PLX3397 (Plexxikon).

[0272] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with a neuroendocrine tumor in combination with temozolomide.

[0273] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in conjunction with gemcitabine to a subject with recurrent or metastatic head or neck cancer.

[0274] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with pancreatic cancer in conjunction with gemcitabine.

[0275] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with colon cancer in combination with ARISA®, avastatin, taxol, and / or taxotere.

[0276] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in conjunction with capecitabine and / or PLX4032 (Plexxikon) to a subject with refractory colorectal cancer or who has failed first-line therapy or has poor disease with colon or rectal adenocarcinoma.

[0277] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with fluorouracil, leucovorin, and irinotecan to a subject with Dukes' C&D colorectal cancer or a subject who has previously been treated for metastatic colorectal cancer.

[0278] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with refractory colorectal cancer in combination with capecitabine, Xeloda, and / or CPT-11.

[0279] In certain embodiments, a compound provided herein, or a derivative thereof, is administered with capecitabine and irinotecan to a subject with refractory colorectal cancer or a subject with unresectable or metastatic colorectal cancer.

[0280] In certain embodiments, a compound provided herein, or a derivative thereof, is administered alone or in combination with interferon alpha or capecitabine to a subject with unresectable or metastatic hepatocellular carcinoma; or in combination with cisplatin and thiotepa to a subject with primary or metastatic liver cancer.

[0281] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with Kaposi's sarcoma in combination with pegylated interferon alpha.

[0282] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with fludarabine, carboplatin, and / or topotecan to a subject with refractory or relapsed or high-risk acute myeloid leukemia.

[0283] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with liposomal daunorubicin, topotecan, and / or cytarabine to a subject with unfavorable karyotype acute myeloblastic leukemia.

[0284] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with non-small cell lung cancer in combination with gemcitabine, abraxane, erlotinib, geftinib, and / or irinotecan.

[0285] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with non-small cell lung cancer in combination with carboplatin and irinotecan.

[0286] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in conjunction with doxetaxol to a subject with non-small cell lung cancer who has previously been treated with carbo / VP16 and radiation therapy.

[0287] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with non-small cell lung cancer in combination with carboplatin and / or taxotere, or in combination with carboplatin, paclitaxel and / or thoracic radiation therapy.

[0288] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with taxotere to a subject with stage IIIB or IV non-small cell lung cancer.

[0289] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with oblimersen (Genasense®) to a subject with non-small cell lung cancer.

[0290] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with ABT-737 (Abbott Laboratories) and / or obatoclax (GX15-070) to subjects with lymphoma and other hematological cancers.

[0291] In certain embodiments, a compound provided herein, or a derivative thereof, alone or in combination with a second active ingredient, such as vinblastine or fludarabine, is administered to a subject with various types of lymphoma, including, but not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, or relapsed or refractory low-grade follicular lymphoma.

[0292] In certain embodiments, compounds provided herein, or derivatives thereof, are administered in combination with taxotere, IL-2, IFN, GM-CSF, PLX4032 (Plexxikon), and / or dacarbazine to subjects with various types or stages of melanoma.

[0293] In certain embodiments, a compound provided herein, or a derivative thereof, alone or in combination with vinorelbine, is administered to a subject with malignant mesothelioma or stage IIIB non-small cell lung cancer with pleural implantation or malignant pleural effusion mesothelioma syndrome.

[0294] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with dexamethasone, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulfan, cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonates, celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a combination thereof to subjects with various types or stages of multiple myeloma.

[0295] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with relapsed or refractory multiple myeloma in combination with doxorubicin (Doxil®), vincristine, and / or dexamethasone (Decadron®).

[0296] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with taxol, carboplatin, doxorubicin, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or a combination thereof to subjects with various types or stages of ovarian cancer, such as peritoneal carcinoma, papillary serous carcinoma, refractory ovarian cancer, or recurrent ovarian cancer.

[0297] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with various types or stages of prostate cancer in combination with Xeloda, 5FU / LV, gemcitabine, irinotecan, as well as gemcitabine, cyclophosphamide, vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, emcit, dendron, or combinations thereof.

[0298] In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with capecitabine, IFN, tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination thereof to subjects with various types or stages of renal cell carcinoma.

[0299] In certain embodiments, compounds provided herein, or derivatives thereof, are administered in combination with IFN, a COX-2 inhibitor such as Celebrex®, and / or sulindac to subjects with various types or stages of gynecological, uterine, or soft tissue sarcoma cancer.

[0300] In certain embodiments, the compounds provided herein, or derivatives thereof, are administered in combination with Celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or combinations thereof to subjects with solid tumors of various types or stages.

[0301] In certain embodiments, a compound provided herein, or a derivative thereof, is administered to a subject with scleroderma or cutaneous vasculitis in combination with Celebrex, etoposide, cyclophosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a combination thereof.

[0302] Also encompassed herein is a method for increasing the dosage of an anti-cancer drug or agent that can be safely and effectively administered to a subject, comprising administering a compound provided herein or a derivative thereof to a subject (e.g., a human).Subjects that can benefit from this method are those who are likely to suffer from adverse effects associated with anti-cancer drugs for treating certain cancers of the skin, subcutaneous tissue, lymph nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas, adrenal gland, kidney, prostate, breast, colorectum, or a combination thereof.Administering a compound provided herein or a derivative thereof alleviates or reduces the adverse effects, the severity of which would otherwise limit the amount of anti-cancer drug.

[0303] In one embodiment, a compound provided herein, or a derivative thereof, is administered orally daily in an amount ranging from about 0.1 to about 150 mg, about 1 to about 50 mg, or about 2 to about 25 mg before, during, or after the onset of adverse effects associated with the administration of an anti-cancer drug to a subject. In certain embodiments, a compound provided herein, or a derivative thereof, is administered in combination with certain agents, such as heparin, aspirin, coumadin, or G CSF, to avoid adverse effects associated with anti-cancer drugs, such as, but not limited to, neutropenia or thrombocytopenia.

[0304] In one embodiment, a compound provided herein, or a derivative thereof, is administered in combination with additional active ingredients, including, but not limited to, anti-cancer drugs, anti-inflammatory agents, antihistamines, antibiotics, and steroids, to a subject having a disease or disorder associated with or characterized by unwanted angiogenesis.

[0305] In another embodiment, encompassed herein are methods for treating, preventing, and / or managing cancer, comprising administering a compound provided herein, or a derivative thereof, in conjunction with (before, during, or after) conventional therapy, including, but not limited to, surgery, immunotherapy, biological therapy, radiation therapy, or other non-drug-based therapy currently used to treat, prevent, or manage cancer. The combination of a compound provided herein, or a derivative thereof, and conventional therapy may provide a unique treatment regimen that is unexpectedly effective in a given subject. Without being limited by theory, it is believed that a compound provided herein, or a derivative thereof, may provide additive or synergistic effects when given simultaneously with conventional therapy.

[0306] As discussed elsewhere herein, encompassed herein are methods for reducing, treating, and / or preventing adverse or undesirable effects associated with conventional therapies, including, but not limited to, surgery, chemotherapy, radiation therapy, hormone therapy, biological therapy, and immunotherapy. The compounds provided herein, or derivatives thereof, and other active ingredients, can be administered to a subject before, during, or after the onset of adverse effects associated with the conventional therapy.

[0307] In one embodiment, a compound provided herein, or a derivative thereof, may be administered orally daily in an amount ranging from about 0.1 to about 150 mg, about 1 to about 25 mg, or about 2 to about 10 mg, either alone or in combination with a second active agent disclosed herein, before, during, or after conventional therapy.

[0308] In certain embodiments, a compound provided herein, or a derivative thereof, and doxetaxol are administered to a subject with non-small cell lung cancer who has previously been treated with carbo / VP16 and radiation therapy.

[0309] In some embodiments, a compound provided herein, or a derivative thereof, is administered in combination with an immunotherapy or combination of immunotherapy agents to a subject with various types or stages of cancer. In one embodiment, a compound provided herein, or a derivative thereof, is administered in combination with Opdivo, Keytruda, Yervoy, or a combination thereof to a subject with various types or stages of cancer.

[0310] 6.3.2 Inflammation As discussed herein, activation of MAPK is a component of the inflammatory response. Therefore, compounds provided herein that are MAPK inhibitors through the inhibition of Ras and / or Ras superfamily members are useful for treating inflammatory diseases.

[0311] In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that inhibits the function of one or more members of the Ras superfamily by binding to the GTP-binding domain or one or more members of the Ras superfamily. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that inhibits the function of Ras by binding to the GTP-binding domain of Ras. In another ... 50 and K<10 μM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 1 μM. 50 and K<1 μM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 500 nM. 50 and K<500 nM dProvided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 470 nM. 50 and K less than 470 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 270 nM. 50 and K less than 270 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 200 nM. 50 and K<200 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 25% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 50% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 75% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 80% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 85% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 90% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 95% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 99% inhibition at 20 μM. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that inhibits the function of Rho by binding to the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that inhibits the function of Rho by binding to the GTP-binding domain of Rho with an IC of less than 10 μM. 50 and K<10 μM dProvided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 1 μM. 50 and K<1 μM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 500 nM. 50 and K<500 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 270 nM. 50 and K less than 270 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 200 nM. 50 and K<200 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 130 nM. 50 and K less than 130 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 25% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 50% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 75% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 80% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 85% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 90% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 95% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 99% inhibition at 20 μM. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that inhibits the function of Rac by binding to the GTP-binding domain of Rac. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, comprising administering to a subject a compound that inhibits the function of Rac by binding to the GTP-binding domain of Rac with an IC of less than 10 μM. 50 and K<10 μM dProvided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 1 μM. 50 and K<1 μM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 500 nM. 50 and K<500 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 270 nM. 50 and K less than 270 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 200 nM. 50 and K<200 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 170 nM. 50 and K less than 170 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 25% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 50% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 75% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 80% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 80% inhibition at 20 μM. Provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 85% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 90% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 95% inhibition at 20 μM. In another embodiment, provided herein are methods for treating or preventing an inflammatory disease, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 99% inhibition at 20 μM.

[0312] In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to four or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to five or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to seven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to eight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to ten or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 11 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 12 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 14 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 15 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 16 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 17 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 18 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 19 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 20 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, a method for treating or preventing an inflammatory disease is provided, comprising administering to a subject a compound that binds to 21 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 22 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 23 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.

[0313] In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to four or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to five or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to seven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to eight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to ten or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 11 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 12 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 14 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 15 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 16 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 17 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 18 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 19 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 20 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, a method for treating or preventing an inflammatory disease, comprising administering to a subject an inflammatory disease ... Provided herein are methods that include administering to a subject a compound that binds to 21 or more of 2, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 22 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 23 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.

[0314] In one embodiment, the Ras is DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2. In another embodiment, the Ras is HRAS, KRAS, or NRAS. In one embodiment, the Ras is HRAS. In one embodiment, the Ras is KRAS. In one embodiment, the Ras is NRAS. In another embodiment, the Ras is a mutant form of Ras described herein.

[0315] In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to one or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to two or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to three or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to four or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to five or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to six or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to seven or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to eight or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to nine or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 10 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to eleven or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 12 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 13 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 14 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 15 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 16 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 17 or more of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to all of Gly14, Ala15, Cys16, Gly17, Lys18, Thr19, Cys20, Phe30, Pro31, Glu32, Tyr34, Val35, Pro36, Thr37, Asp59, Lys118, Asp120, Lys162, or Mg202 in the GTP-binding domain of Rho.

[0316] In one embodiment, Rho is RHOA; RHOB; RHOBTB1; RHOBTB2; RHOBTB3; RHOC; RHOD; RHOF; RHOG; RHOH; RHOJ; RHOQ; RHOU; RHOV; RND1; RND2; RND3; RAC1; RAC2; RAC3 or CDC42. In one embodiment, Rho is RHOA. In another embodiment, Rho is a mutant form of Rho described herein.

[0317] In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to one or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to two or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to three or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to four or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to five or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to six or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to seven or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to eight or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to nine or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 10 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to eleven or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 12 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 13 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 14 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 15 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 16 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 17 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to 18 or more of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac. In one embodiment, provided herein is a method for treating or preventing an inflammatory disease, the method comprising administering to a subject a compound that binds to all of Gly12, Ala13, Gly15, Lys16, Thr17, Cys18, Leu19, Phe28, Ile33, Pro34, Val36, Ala59, Thr115, Lys116, Asp118, Leu119, Cys157, Ala159, or Mg202 in the GTP-binding domain of Rac.

[0318] In one embodiment, Rho is Rac. In one embodiment, Rac is RAC1; RAC2; RAC3 or RHOG. In one embodiment, Rac is RAC1. In another embodiment, Rac is a mutant form of Rac described herein.

[0319] In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to one or more members of the Ras superfamily. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Ras. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Rho. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Rac. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Ras and Rho. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Ras and Rac. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Rho and Rac. In one embodiment, the compounds used in the methods and compositions provided herein inhibit GTP binding to Ras, Rho, and Rac.

[0320] In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 2000 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1750 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1500 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1250 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 1000 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 750 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 665 daltons. In one embodiment, the compounds used in the methods and compositions provided herein have a molecular weight of less than 500 daltons. In another embodiment, the compounds used in the methods and compositions provided herein contain an oxadiazole, thiadiazole, or triazole moiety. In another embodiment, the compound used in the methods and compositions provided herein contains a 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole moiety, 2-acylaminothiazole, 2-(pyridin-2-yl)pyrimidin-4-amine, 2-(pyridin-2-yl)pyrimidin-4-ol, 2-(pyridin-2-yl)pyrimidin-4-(1H)-one, 2-(pyridin-2-yl)pyrimidin-4(3H)-one, 2-(pyridin-2-yl)pyrimidin-4(1H)-imine, or 2-(pyridin-2-yl)pyrimidin-4(3H)-imine moiety.In another embodiment, the compound used in the methods and compositions provided herein is 2-(pyridin-2-yl)pyrimidin-4-amine, 2-(pyridin-2-yl)pyrimidin-4-ol, 2-(pyridin-2-yl)pyrimidin-4-(1H)-one, 2-(imidazol-2-yl)pyrimidin-4-ol, 2-(imidazol-2-yl)pyrimidin-4(3H)-one, 2-(imidazol-2-yl)pyrimidin-4(1H)-one, 2-(imidazol-2-yl)pyrimidin-4-amine, 2-(imidazole 2-(imidazol-4-yl)pyrimidin-4(3H)-imine, 2-(imidazol-2-yl)pyrimidin-4(1H)-imine, 2-(imidazol-4-yl)pyrimidin-4-ol, 2-(imidazol-4-yl)pyrimidin-4(3H)-one, 2-(imidazol-4-yl)pyrimidin-4(1H)-one, 2-(imidazol-4-yl)pyrimidin-4-amine, 2-(imidazol-4-yl)pyrimidin-4(3H)-imine, or 2-(imidazol-4-yl)pyrimidin-4(1H)-imine moiety.

[0321] In one embodiment, the inflammatory disease is the development of cancer associated with inflammation. As disclosed herein, the compounds provided herein are useful for treating cancer. It is well recognized that immune-inflammatory states function as important mediators in the mid-stage of tumor growth. It is also well known that chronic inflammation predisposes individuals to cancer. Chronic inflammation can be caused by a variety of factors, including bacterial, viral, and parasitic infections. The longer inflammation persists, the higher the associated risk of cancer development. Anti-inflammatory cancer therapy prevents precancerous cells from becoming fully cancerous or prevents existing tumors from spreading to distant sites in the body. Therefore, in one embodiment, the compounds provided herein are useful for treating inflammatory cancer. Such cancers and chronic inflammatory conditions that predispose susceptible cells to neoplastic transformation include gastric adenocarcinoma (gastritis), mucosa-associated lymphoid tissue (MALT) lymphoma (gastritis), bladder, liver, and rectal cancer (schistosomiasis), bile duct and colon cancer (cholangitis), gallbladder cancer (chronic cholecystitis), ovarian and cervical cancer (pelvic inflammatory disease, chronic cervicitis), skin cancer (osteomyelitis), colorectal cancer (inflammatory bowel disease), and others. These include esophageal cancer (reflux esophagitis, Barrett's esophagus), bladder cancer (bladder inflammation (cystitis)), mesothelioma and lung cancer (asbestosis, silicosis), oral squamous cell carcinoma (gingivitis, lichen planus), pancreatic cancer (pancreatitis, protease mutation), vulvar squamous cell carcinoma (lichen sclerosus), salivary gland cancer (sialadenitis), lung cancer (bronchitis), and MALT lymphoma (Sjögren's syndrome, Hashimoto's thyroiditis). Shacter, et al., 2002, Oncology, 16(2), 217-26.

[0322] In certain embodiments, the compounds provided herein are useful for treating inflammatory diseases in the airways, such as nonspecific bronchial hyperresponsiveness, chronic bronchitis, cystic fibrosis, and acute respiratory distress syndrome (ARDS).

[0323] In certain embodiments, the compounds provided herein are useful for treating asthma and idiopathic pulmonary fibrosis or idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis, and interstitial lung disease. As known to those skilled in the art, differentiation of fibroblasts into a cell type called myofibroblasts occurs during wound healing, when the cells contribute to the deposition of extracellular matrix (ECM) in the transient process of wound repair. In chronic inflammatory diseases such as asthma, pathological tissue remodeling often occurs and is mediated by the function of increased numbers of myofibroblasts in affected tissues. See Hinz, B. et al. Am J Pathol. 2007;170:1807-1816. In certain embodiments, the compounds provided herein prevent or reduce TGF-β-induced myofibroblast differentiation as measured by expression of alpha-smooth muscle actin (α-SMA), a hallmark of myofibroblast differentiation (Serini, G. and Gabbiani, G. 1999; Exp. Cell Res. 250:273-283).

[0324] In certain embodiments, the compounds provided herein are useful for treating psoriasis, chronic plaque psoriasis, psoriatic arthritis, acanthosis, atopic dermatitis, various forms of eczema, contact dermatitis (including allergic dermatitis), systemic sclerosis (scleroderma), wound healing, and drug rash.

[0325] In one embodiment, the disease is inflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, juvenile arthritis and other arthritic conditions, systemic lupus erythematosus (SLE), skin-related conditions, eczema, Sjogren's syndrome, burns, dermatitis, neuroinflammation, allergic pain, autoimmune myositis, neuropathic pain, fever, lung disorders, pulmonary inflammation, adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicosis, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD), cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction conditions), thrombosis, congestive heart failure, cardiac reperfusion injury. and complications associated with hypertension and / or heart failure, such as vascular organ damage, restenosis, cardiomyopathy, stroke including ischemic and hemorrhagic stroke, reperfusion injury, renal reperfusion injury, ischemia including stroke and cerebral ischemia, and ischemia due to cardiac / coronary artery bypass, neurodegenerative disorders, liver disease and nephritis, gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, ulcer disease, gastric ulcer, viral and bacterial infections, sepsis, septic shock, gram-negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, acquired immune Cachexia secondary to AIDS, AIDS, AIDS-related complications, pneumonia, herpes viruses, myalgia due to infection, influenza, autoimmune diseases, graft-versus-host reaction and allograft rejection, treatment of bone resorption disorders, osteoporosis, multiple sclerosis, acute gout, pneumonia, myocarditis, pericarditis, myositis, eczema, alopecia, vitiligo, bullous skin diseases, atherosclerosis, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type 1 diabetes, giant cell arteritis, nephritis including lupus nephritis, glomerulonephritis Vasculitis with organ dysfunction such as nephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, polyarteritis nodosa, Behçet's disease, Kawasaki disease, Takayasu's arteritis, vasculitis with organ dysfunction, acute rejection of transplanted organs, endotoxemia, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, postoperative syndrome, sarcoidosis, Herxheimer reaction, encephalitis, myelitis, SIRS associated with viral infections such as influenza, shingles, herpes simplex,Coronavirus or dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

[0326] In certain embodiments, the compounds provided herein are useful for treating chronic or acute neuropathic and nociceptive pain, including, but not limited to, allodynia, inflammatory pain, inflammatory hyperalgesia, post-herpetic neuralgia, neuropathy, neuralgia, diabetic neuropathy, HIV-associated neuropathy, nerve injury, rheumatoid arthritis pain, osteoarthritis pain, burns, back pain, eye pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, post-operative pain, post-stroke pain, and menstrual pain.

[0327] In certain embodiments, the compounds provided herein are useful for treating reduced CNS function associated with Alzheimer's disease (AD), mild cognitive impairment (MCI), age-associated memory impairment (AAMI), multiple sclerosis, Parkinson's disease, vascular dementia, senile dementia, AIDS dementia, Pick's disease, dementia caused by cerebrovascular accidents, corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, and traumatic brain injury.

[0328] In one embodiment, the compounds provided herein are useful for treating Alzheimer's disease (AD), ankylosing spondyloarthritis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease, ulcerative colitis.

[0329] When used to treat inflammatory diseases, the compounds provided herein can be administered at the dosages, by routes of administration, and / or to achieve the pK profiles described herein for the treatment of cancer.

[0330] 6.3.3 Rasopathy As discussed herein, Ras signaling is causally involved in rasopathy. Therefore, compounds provided herein that inhibit the function of one or more members of the Ras superfamily are useful for treating rasopathy, including neurofibromatosis type 1, Noonan syndrome, and Costello syndrome.

[0331] In one embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that inhibits the function of one or more members of the Ras superfamily by binding to the GTP-binding domain or one or more members of the Ras superfamily. In one embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that inhibits the function of Ras by binding to the GTP-binding domain of Ras. In another ... with an IC of less than 10 μM. 50 and K<10 μM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 1 μM. 50 and K<1 μM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 500 nM. 50 and K<500 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 470 nM. 50 and K less than 470 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 270 nM. 50 and K less than 270 nM dProvided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC50 of less than 200 nM. 50 and K<200 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras at an IC of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods that include administering to a subject a compound that binds to the GTP-binding domain of Ras at the In another embodiment, the method of treating or preventing rasopathy comprises administering an IC of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 25% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 50% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 75% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 80% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 85% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 90% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 95% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Ras with greater than 99% inhibition at 20 μM. In one embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that inhibits the function of Rho by binding to the GTP-binding domain of Rho. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that inhibits the function of Rho by binding to the GTP-binding domain of Rho with an IC of less than 10 μM. 50 and K<10 μM dProvided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC of less than 1 μM. 50 and K<1 μM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC50 of less than 500 nM. 50 and K<500 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC50 of less than 270 nM. 50 and K less than 270 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC50 of less than 200 nM. 50 and K<200 nM d Provided herein are methods that include administering to a subject a compound that binds to the GTP-binding domain of Rho at the In another embodiment, the method of treating or preventing rasopathy comprises administering an IC of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC50 of less than 130 nM. 50 and K less than 130 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho at an IC50 of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 25% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 50% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 75% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 80% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 85% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 90% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 95% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rho with greater than 99% inhibition at 20 μM. In one embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that inhibits the function of Rac by binding to the GTP-binding domain of Rac. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that inhibits the function of Rac by binding to the GTP-binding domain of Rac. 50 and K<10 μM dProvided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 1 μM. 50 and K<1 μM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 500 nM. 50 and K<500 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 270 nM. 50 and K less than 270 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC50 of less than 200 nM. 50 and K<200 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC50 of less than 170 nM. 50 and K less than 170 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC of less than 150 nM. 50 and K less than 150 nM d Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac at an IC50 of less than 100 nM. 50 and K<100 nM dProvided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 25% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 50% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 75% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 80% inhibition at 20 μM. Provided herein are methods for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 85% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 90% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 95% inhibition at 20 μM. In another embodiment, provided herein is a method for treating or preventing rasopathy, comprising administering to a subject a compound that binds to the GTP-binding domain of Rac with greater than 99% inhibition at 20 μM.

[0332] In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to four or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to five or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to seven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to eight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to ten or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 11 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 12 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to thirteen or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 14 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 15 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 16 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 17 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 18 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 19 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 20 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 21 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 22 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to 23 or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, Lys147, or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to all of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.

[0333] In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to one or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to two or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to three or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to four or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to five or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to six or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to seven or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to eight or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to nine or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras. In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compound that binds to ten or more of Ala11, Gly12, Val14, Gly15, Lys16, Ser17, Ala18, Phe28, Val29, Asp30, Glu31, Tyr32, Asp33, Pro34, Thr35, Lys36, Gly60, Gln61, Lys117, Asp119, Leu120, Ser145, Ala146, and Lys147 or Mg202 in the GTP-binding domain of Ras.In another embodiment, provided herein is a method for treating or preventing rasopathy, the method comprising administering to a subject a compo...

Claims

【Request 1】 【Chemistry 2】 or a pharma- ceutically acceptable salt or tautomer thereof. 【Request 2】 【Chemical 4】 or a pharma- ceutically acceptable salt or tautomer thereof.

3. Formula VIb1: 【Chemistry 5】 or a pharma- ceutically acceptable salt or tautomer thereof, (In the formula, R １ｂ１ is imidazolyl, N-methyl-2-imidazolyl, N-methyl-4-imidazolyl, 2-pyrimidinyl or 4-pyrimidinyl; R ８ｂ１ is H or alkyl; R ９ｂ１ is aryl, heteroaryl, heterocyclyl, halo, cyano, thiocyanate, selenocyanate, trifluoromethoxy, azido, C(O)R ４ , or S(O) ｐ R ４ and R ４ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or -NR ６ R ７ and R ６ and R ７ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl, or alkylsulfonyl, or R ６ and R ７ combine to form a ring structure containing the nitrogen atom to which they are both attached; p is 0 to 2; Each alkyl, aryl, heteroaryl, heterocyclyl, haloalkyl, alkenyl, alkynyl, alkylaryl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl or alkylsulfonyl in R 4 , R 6 or R 7 is optionally substituted with one or more substituents Q, each Q being independently selected from: (a) deuterium, cyano, halo, and nitro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ６－１４ Aryl, C ７－１５ Aralkyl, heteroaryl, and heterocyclyl, each of which may contain one or more, in one embodiment one, two, three, or four, substituents Q ａ and (c) -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , -C(NR ａ ) N.R. ｂ R ｃ , -OR ａ , -OC(O)R ａ , -OC(O)OR ａ , -OC(O)NR ｂ R ｃ , -OC(=NR ａ ) N.R. ｂ R ｃ , -OS(O)R ａ , -OS(O) ２ R ａ , -OS(O)NR ｂ R ｃ , -OS(O) ２ N.R. ｂ R ｃ , -NR ｂ R ｃ , -NR ａ C(O)R ｄ , -NR ａ C(O)OR ｄ , -NR ａ C(O)NR ｂ R ｃ , -NR ａ C (=NR ｄ ) N.R. ｂ R ｃ , -NR ａ S(O)R ｄ , -NR ａ S (O) ２ R ｄ , -NR ａ S(O)NR ｂ R ｃ , -NR ａ S (O) ２ N.R. ｂ R ｃ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ｂ R ｃ , and -S(O) ２ N.R. ｂ R ｃ (Each R ａ , R ｂ , R ｃ , and R ｄ are independently: (i) hydrogen or deuterium; (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl (each of which may contain one or more, in one embodiment one, two, three, or four, substituents Q ａ or (iii) R ｂ and R ｃ together with the N atom to which they are attached, one or more, in one embodiment one, two, three or four, substituents Q ａ forming a heterocyclyl optionally substituted with ａ are independently: (a) deuterium, cyano, halo, and nitro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｆ R ｇ , -C(NR ｅ ) N.R. ｆ R ｇ , -OR ｅ , -OC(O)R ｅ , -OC(O)OR ｅ , -OC(O)NR ｆ R ｇ , -OC(=NR ｅ ) N.R. ｆ R ｇ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｆ R ｇ , -OS(O) ２ N.R. ｆ R ｇ , -NR ｆ R ｇ , -NR ｅ C(O)R ｈ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｆ R ｇ , -NR ｅ C (=NR ｈ ) N.R. ｆ R ｇ , -NR ｅ S(O)R ｈ , -NR ｅ S (O) ２ R ｈ , -NR ｅ S(O)NR ｆ R ｇ , -NR ｅ S (O) ２ N.R. ｆ R ｇ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｆ R ｇ , and -S(O) ２ N.R. ｆ R ｇ each R ｅ , R ｆ , R ｇ , and R ｈ are independently: (i) hydrogen or deuterium; (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ｆ and R ｇ together with the N atom to which they are attached form a heterocyclyl. A compound.

4. Compound of formula VIb1: 【Chemistry 6】 or a pharma- ceutically acceptable salt or tautomer thereof (In the formula, R １ｂ１ is heteroaryl, where heteroaryl is pyridyl, imidazolyl, N-methyl-2-imidazolyl, N-methyl-4-imidazolyl, 2-pyrimidinyl, or 4-pyrimidinyl; R ８ｂ１ is H or alkyl; R ９ｂ１ is cycloalkyl).

5. R １ｂ１ 5. The compound of claim 4, or a pharma- ceutically acceptable salt or tautomer thereof, wherein: is pyridyl.

6. R １ｂ１ 6. The compound of claim 4 or claim 5, or a pharma- ceutically acceptable salt or tautomer thereof, wherein: is imidazolyl.

7. Compound of formula VIb1: 【Chemistry 7】 or a pharma- ceutically acceptable salt or tautomer thereof (In the formula, R １ｂ１ is pyridyl; R ８ｂ１ is alkyl; R ９ｂ１ is phenyl, heteroaryl, heterocyclyl, fluoro, chloro, iodo, C(O)R ４ , or S(O) ｐ R ４ wherein said heteroaryl group is not a substituted pyrazole; R ４ is hydrogen, hydroxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, or -NR ６ R ７ and R ６ and R ７ is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl, or alkylsulfonyl, or R ６ and R ７ combine to form a ring structure containing the nitrogen atom to which they are both attached; p is 0 to 2; or R １ｂ１ is 2-pyridyl; R ８ｂ１ is H; R ９ｂ１ is heteroaryl or heterocyclyl, said heteroaryl group not being a substituted pyrazole; And, Each alkyl, heteroaryl, heterocyclyl, haloalkyl, alkenyl, alkynyl, aryl, alkylaryl, cycloalkyl, aralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkylaryloxy, heterocyclyloxy, cycloalkyloxy, aralkoxy, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, arylsulfonyl, heteroarylsulfonyl, cycloalkylsulfonyl, or alkylsulfonyl in R 4 , R 6 , R 7 , or R 9b1 is optionally substituted with one or more substituents Q, each Q being independently selected from: (a) deuterium, cyano, halo, and nitro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ６－１４ Aryl, C ７－１５ Aralkyl, heteroaryl, and heterocyclyl, each of which may contain one or more, in one embodiment one, two, three, or four, substituents Q ａ and (c) -C(O)R ａ , -C(O)OR ａ , -C(O)NR ｂ R ｃ , -C(NR ａ ) N.R. ｂ R ｃ , -OR ａ , -OC(O)R ａ , -OC(O)OR ａ , -OC(O)NR ｂ R ｃ , -OC(=NR ａ ) N.R. ｂ R ｃ , -OS(O)R ａ , -OS(O) ２ R ａ , -OS(O)NR ｂ R ｃ , -OS(O) ２ N.R. ｂ R ｃ , -NR ｂ R ｃ , -NR ａ C(O)R ｄ , -NR ａ C(O)OR ｄ , -NR ａ C(O)NR ｂ R ｃ , -NR ａ C (=NR ｄ ) N.R. ｂ R ｃ , -NR ａ S(O)R ｄ , -NR ａ S (O) ２ R ｄ , -NR ａ S(O)NR ｂ R ｃ , -NR ａ S (O) ２ N.R. ｂ R ｃ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ｂ R ｃ , and -S(O) ２ N.R. ｂ R ｃ (Each R ａ , R ｂ , R ｃ , and R ｄ are independently: (i) hydrogen or deuterium; (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl (each of which may contain one or more, in one embodiment one, two, three, or four, substituents Q ａ or (iii) R ｂ and R ｃ together with the N atom to which they are attached, one or more, in one embodiment one, two, three or four, substituents Q ａ forming a heterocyclyl optionally substituted with ａ is, independently, (a) deuterium, cyano, halo, and nitro; (b) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R ｅ , -C(O)OR ｅ , -C(O)NR ｆ R ｇ , -C(NR ｅ ) N.R. ｆ R ｇ , -OR ｅ , -OC(O)R ｅ , -OC(O)OR ｅ , -OC(O)NR ｆ R ｇ , -OC(=NR ｅ ) N.R. ｆ R ｇ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｆ R ｇ , -OS(O) ２ N.R. ｆ R ｇ , -NR ｆ R ｇ , -NR ｅ C(O)R ｈ , -NR ｅ C(O)OR ｆ , -NR ｅ C(O)NR ｆ R ｇ , -NR ｅ C (=NR ｈ ) N.R. ｆ R ｇ , -NR ｅ S(O)R ｈ , -NR ｅ S (O) ２ R ｈ , -NR ｅ S(O)NR ｆ R ｇ , -NR ｅ S (O) ２ N.R. ｆ R ｇ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｆ R ｇ , and -S(O) ２ N.R. ｆ R ｇ each R ｅ , R ｆ , R ｇ , and R ｈ are independently: (i) hydrogen or deuterium; (ii) C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－７ Cycloalkyl, C ６－１４ Aryl, C ７－１５ aralkyl, heteroaryl, or heterocyclyl; or (iii) R ｆ and R ｇ together with the N atom to which they are attached form a heterocyclyl). 【Request 8】 【Chemical 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 or a pharma- ceutically acceptable salt or tautomer thereof.

9. 【Chemical 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 or a pharma- ceutically acceptable salt or tautomer thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt or tautomer thereof, and a pharma- ceutically acceptable carrier, diluent or excipient.

11. 10. Use of a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt or tautomer thereof, in the manufacture of a medicament for treating cancer, an inflammatory disease, a rasopathy, or a fibrotic disease in a subject in need thereof, wherein the compound, or a pharma- ceutically acceptable salt or tautomer thereof, inhibits the function of one or more members of the Ras superfamily.

12. 2. Use of a compound or a pharmaceutically acceptable salt or tautomer thereof in the manufacture of a medicament for treating cancer, an inflammatory disease, a rasopathy, or a fibrotic disease in a subject in need thereof, wherein the compound or a pharmaceutically acceptable salt or tautomer thereof inhibits the function of one or more members of the Ras superfamily, and wherein the compound is 【Chemistry 24-1】 or 【Chemistry 24-2】 or a pharma- ceutically acceptable salt or tautomer thereof.

13. 13. The use according to claim 11 or claim 12, wherein the cancer is blood cancer, hepatocellular carcinoma, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, small intestine cancer, biliary tract cancer, endometrial cancer, skin cancer (melanoma), cervical cancer, urinary tract cancer, or glioblastoma.

14. 13. The use according to claim 11 or claim 12, wherein the inflammatory disease is gastritis, schistosomiasis, cholangitis, chronic cholecystitis, pelvic inflammatory disease, chronic cervicitis, osteomyelitis, inflammatory bowel disease, reflux esophagitis, Barrett's esophagus, bladder inflammation (cystitis), asbestosis, silicosis, gingivitis, lichen planus, pancreatitis, protease mutation, lichen sclerosus, sialadenitis, bronchitis, Sjogren's syndrome, Hashimoto's thyroiditis, Alzheimer's disease (AD), ankylosing spondyloarthritis, arthritis (osteoarthritis, rheumatoid arthritis (RA), psoriatic arthritis), asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus, lupus erythematosus (SLE), nephritis, Parkinson's disease, or ulcerative colitis.

15. 13. The use according to claim 11 or claim 12, wherein the rasopathies are neurofibromatosis type 1, Noonan syndrome or Costello syndrome.

16. The use according to any one of claims 11 to 15, wherein the one or more members of the Ras superfamily are Ras proteins.

17. 17. The use of claim 16, wherein the compound inhibits GTP binding to the Ras protein GTP-binding domain with greater than 25% inhibition at 20 μM in a cell-free assay.

18. 18. The use according to claim 17, wherein the Ras protein is HRAS, KRAS, or NRAS, or a mutant thereof.

19. 10. A composition comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or tautomer thereof, for treating cancer, an inflammatory disease, a rasopathy, or a fibrotic disease in a subject in need thereof, wherein the compound, or a pharmaceutically acceptable salt or tautomer thereof, inhibits the function of one or more members of the Ras superfamily.

20. 1. A composition comprising a compound or a pharmaceutically acceptable salt or tautomer thereof for treating cancer, an inflammatory disease, a rasopathy, or a fibrotic disease in a subject in need thereof, wherein the compound or a pharmaceutically acceptable salt or tautomer thereof inhibits the function of one or more members of the Ras superfamily, and wherein the compound is 【Chemistry 25-1】 or 【Chemistry 25-2】 or a pharma- ceutically acceptable salt or tautomer thereof.

Images