Combination therapy for treatment of cancer

Abstract

Disclosed are novel compounds for use in treating a proliferative disorder such as a cancer. Further disclosed are compositions comprising the novel compounds. Methods of using the disclosed compounds and compositions are further described. The methods include administering one or more of the disclosed compounds for treatment of various proliferative disorders, including an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer. Further described are combination therapies in which a novel compound is administered in combination with one or more of a MEK inhibitor, a KRAS G12C inhibitor, or a Selective Estrogen Receptor Degrader (SERD) to an individual in need thereof.

Description

2023-1007cCOMBINATION THERAPY FOR TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present patent application claims priority to U.S. Provisional Application No. 63 / 723.191 filed November 21, 2024, the contents of which are incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH

[0002] This invention was made with government support under CA237016 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Cancer remains one of the leading causes of death worldwide, with millions of new cases diagnosed annually. Among the various molecular drivers of cancer, mutations in the RAS family of proteins, including HRAS, KRAS, and NRAS, are found in approximately 20-30% of human cancers. These proteins function as molecular switches that regulate cell growth, differentiation, and survival pathways. KRAS mutations are particularly prevalent in certain cancer types, including pancreatic adenocarcinoma, colorectal cancer, and non- small cell lung cancer. In hematologic malignancies, KRAS mutations are also observed in various leukemias, including B- cell acute lymphoblastic leukemia (B-ALL). The presence of oncogenic RAS mutations is frequently associated with poor prognosis and resistance to conventional therapies.

[0004] Current therapeutic approaches for RAS-driven cancers include targeted inhibitors such as KRAS G12C inhibitors such as sotorasib and adagrasib, which have shown clinical efficacy in specific patient populations. Additionally, MEK inhibitors such as trametinib, cobimetinib, and binimetinib target the RAF-MEK-ERK cascade downstream of RAS. However, these treatments often face challenges including acquired resistance, limited efficacy across different RAS mutants, and dose-limiting toxicides. Thus, there remains a continued need for treatments that can effectively target cancers, such as RAS-driven cancers, across multiple mutation types and cancer lineages.2023-1007CBRIEF SUMMARY

[0005] Disclosed are novel compounds for use in treating a proliferative disorder such as a cancer. Further disclosed are compositions comprising the novel compounds. Methods of using the disclosed compounds and compositions are further described. The methods include administering one or more of the disclosed compounds for treatment of various proliferative disorders, including an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone- resistant triple negative breast cancer. Further described are combination therapies in which a novel compound is administered in combination with one or more of a MEK inhibitor, a KRAS G12C inhibitor, or a Selective Estrogen Receptor Degrader (SERD) to an individual in need thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] This application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0007] Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

[0008] FIG. 1 depicts the structure of IODVA1 and derivatives thereof.

[0009] FIG. 2 depicts the synthesis of IODVA1B analogs. Representative R-groups are shown in Table 1.

[0010] FIG. 3 depicts a schematic of testing used to determine VAV3 binding to Compound 3-007.

[0011] FIG. 4 depicts a pulldown of rVAV3 with biotinylated IODVA1.2023-1007C

[0012] FIG. 5 depicts the survival of Ba / F3 leukemic cells expressing the pl90-BCR-ABL oncogene in response to Compound 3-007.

[0013] FIG. 6 depicts a blot in which expression of pVAV3, Vav3, and HA-tag is detected (GAPDH used as a control; pan-RAS to confirm KRAS was not overexpressed) (top panel) and a schematic of the mechanism of KRAS activation of VAV3 (bottom panel).

[0014] FIG. 7A depicts % survival in mice in response to vehicle, sotorasib, trametinib, Compound 3-007, sotorasib + trametinib, sotorasib + Compound 3-007, and trametinib + Compound 3-007. FIG. 7B depicts the percentage of leukemic cells (F4 / 80 and B220 positive) in peripheral blood post-transplant in response to the listed treatments.

[0015] FIG. 8A depicts the % survival in response to the listed treatments; FIG. 8B depicts the leukemic burden count in response to the listed treatments.

[0016] FIG. 9 depicts the % of phospho-positive cells in response to vehicle, trametinib, Compound 3-007 and the combination of Compound 3-007 and trametinib.

[0017] FIG. 10 is a schematic of the proposed interaction of trametinib and Compound 3-007 on the VAV3 / RAC / PAK1 pathway.

[0018] FIG. 11 shows % viability in response to Compound 3-007 in lung papillary adenocarcinoma (top) and lung mucoepidermoid carcinoma (bottom).

[0019] FIG. 12 shows the percentage inhibition of Compound 3-007 in 485 wild-type and mutant kinases.

[0020] FIG. 13 depicts the -log 10(q- value) and effect size, for various doses of Compound 3- 007.

[0021] FIG. 14 depicts survival curves of KRAS-driven B-ALL in response to vehicle, 3-007, and 3-007 / T1 + Fulvestrant / T2. Panel A depicts the results in the context of KRASG12V. Panel B depicts the results in the context of KRASG13D.2023-1007c

[0022] FIG. 15A-15B depict plots of the AUC for cancer cell lines grouped by their lineage. Dotted horizontal line represents average AUC value for all cell lines. Lineages highlighted with a red star are most sensitive to 3-007.DETAILED DESCRIPTION

[0023] The following description sets forth exemplary aspects of the present disclosure. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure. Rather, the description also encompasses combinations and modifications to those exemplary aspects described herein.

[0024] In brief, a small molecule referred to herein as Compound 3-007 has been developed with cellular inhibitory activity against several transformed cell lines including RAS -driven cell lines. Compound 3-007 shows in vivo efficacy and potency against patient-derived xenograft mouse models of relapsed B-cell acute lymphoblastic leukemia (B-ALL) including KRAS-driven B-ALL. Compound 3-007 synergizes with FDA-approved drugs such as trametinib and fulvestrant to prolong the survival of mice models of cancer beyond treatment stoppage. Applicants also synthesized analogs of compound 3-007 with efficacy against cellular models of cancer.

[0025] The present disclosure relates to novel chemical compounds, combinations of compounds, and compositions for treating a proliferative disorder such as a cancer. In aspects, the compounds are characterized by an imidazole-containing core structure with various substituent groups that provide therapeutic activity against proliferating cells such as cancer cells. The compositions may comprise these compounds along with pharmaceutically acceptable excipients to form suitable dosage forms and optional secondary actives for administration to patients.

[0026] In aspects, the compounds described herein, alone or in combination with a second active, may exhibit activity against various types of cancer, including but not limited to leukemia, lung cancer, breast cancer, and Ewing sarcoma. In some cases, the compounds may be particularly effective against cancers driven by mutations in RAS family proteins, including KRAS, HRAS, and NR AS mutations. In aspects, the compounds may be particularly effective against a cancer2023-1007C when combined with a second active as described herein, as compared to administration with a single active, i.e., in aspects, synergy using the described compounds is observed.

[0027] In aspects, disclosed are pharmaceutical compositions comprising the novel compounds and methods of using such compositions to treat a proliferative disorder such as a cancer in an individual in need thereof. In aspects, the compounds may be administered as monotherapy. In other aspects, the compounds may be administered in combination with other therapeutic agents, such as Selective Estrogen Receptor Degrader (SERD), MEK inhibitors, KRAS inhibitors, or other standard-of-care treatments for cancer.

[0028] IODVA1 (FIG. 1. upper structure) is described in the art, for example as detailed in U.S. Patent Publication No. 20230129271, to Nassar et al., published April 27, 2023. Disclosed herein are novel chemical entities that are modified analogs of IODVA1 (see, e.g., FIG. 1, lower structure and table, and FIG. 2). Applicant has found that at least one analog (e.g., Compound 3- 007) is efficacious in the treatment of proliferative disorders such as a cancer. In particular, Applicant has found that Compound 3-007, in which (Ri= ChiChs, A = N, R4, R5, Re, and R7 = H) is superior to FDA-approved and standard of care sotorasib and trametinib in relapsed / recurrent PDX models of leukemia and synergizes with various actives such as trametinib and fulvestrant to achieve an improved therapeutic outcome.

[0029] Further disclosed herein are methods of treating an individual having, or likely to have, a proliferative disorder such as a cancer, comprising administering a compound or pharmaceutical composition as described herein, to the individualCOMPOSITIONS

[0030] In one aspect, a composition is provided. As depicted in FIG. 1, various compounds were synthesized based on the lODVAlb compound. Table 1 depicts.

[0031] Table 1. Derivatives of IODVA1B and their efficacy on breast cancer cells. List of the synthesized IODVA1B analogs compounds tested against breast cancer cells MCF7 (ER+) and MDA-MB-231 (triple negative breast cancer). Cells were plated in 96-well plates in two independent experiments for 24 or 48 hours before they were treated with the indicated compound. Cell viability was read after 7 days incubation. Growth inhibition at 50% (GI50) for each2023-1007C experiment and their average are reported as well as the percentage of cells that were still viable at the end of the 7 -day treatment.2023-1007c

[0032] In aspects, the disclosed composition comprises a compound having a structure as provided in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In one aspect, the composition comprises a compound having a structure of Compound 3-007, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In one aspect, the therapeutic active of the composition consists of, or consists essentially of a compound of Table 1. In one aspect, the therapeutic active of the composition consists of, or consists essentially of Compound 3-007. In one aspect, the therapeutic active of the2023-1007C composition consists of, or consists essentially of Compound 3-006. Pharmaceutically acceptable excipients will be generally understood by one of ordinary skill in the art.

[0033] In one aspect, the composition comprises a combination of actives. For example, in one aspect, the composition comprises, consists of, or consists essentially of a compound of Table 1 and a MEK inhibitor. In one aspect, the composition comprises, consists of, or consists essentially of Compound 3-007 and a MEK inhibitor. Exemplary MEK inhibitors include, but are not limited to trametinib (brand name “Mekinist”), cobimetinib (brand name “Cotellic”), binimetinib (brand name “Mektovi”), selumetinib (brand name “Koselugo”), mirdametinib (brand name “Gomekli”), PD 0325901, and TAK 733. In one aspect, the MEK inhibitor is trametinib. In a further aspect, the composition comprises a combination of actives but excludes a MEK inhibitor.

[0034] In one aspect, the composition comprises a combination of actives, for example, a compound of Table 1 and a KRAS G12C inhibitor. In one aspect, the composition comprises, consists of, or consists essentially of Compound 3-007 and a KRAS G12C inhibitor. Exemplary KRAS G12C inhibitors include, but are not limited to Sotorasib (brand name Lumakras), Adagrasib (brand name Krazati), Divarasib (also known as GDC-6036), MK 1084 (a “nextgeneration” KRAS G12C inhibitor) and combinations thereof. In one aspect, the KRAS G12C inhibitor is sotorasib. In a further aspect, the combination excludes a MEK inhibitor.

[0035] In one aspect, the composition comprises a combination of actives, for example, a compound of Table 1 and a Selective Estrogen Receptor Degrader (SERD). In one aspect, the composition comprises, consists of, or consists essentially of Compound 3-007 and a Selective Estrogen Receptor Degrader (SERD). Exemplary Selective Estrogen Receptor Degraders (SERDs) include, but are not limited to fulvestrant (brand name Faslodex), elacestrant (brand name Orserdu), imlunestrant (brand name Inluriyo), camizestrant (also known as AZD9833), giredestrant (also known as GDC-9545), amcenestrant (also known as SAR439859). bexirestrant, rintodestrant (G1T48), and combinations thereof. In one aspect, the SERD is fulvestrant. In a further aspect, the combination excludes a MEK inhibitor.

[0036] In a yet further aspect, the composition comprises a combination of actives comprising a compound of Table 1, and at least two of, or at least three of the following: a MEK inhibitor, a KRAS G12C inhibitor, and a SERD.2023-1007CComposition Formulations

[0037] The compositions may be formulated with pharmaceutically acceptable excipients that are compatible with all active ingredients present in the formulation. The excipients may be selected to maintain the stability of each active component while providing appropriate pharmaceutical properties for the intended dosage form. The excipient selection may consider potential interactions between different active ingredients and may include stabilizers or other additives to prevent degradation or incompatibility issues.

[0038] For oral dosage forms, the compositions may include excipients such as microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, povidone, magnesium stearate, or other components suitable for tablet or capsule formulations. The excipients may be selected to provide appropriate disintegration, dissolution, and bioavailability characteristics for each active ingredient. The formulation may include enteric coatings or other specialized coatings to control drug release or protect sensitive active ingredients from degradation.

[0039] For injectable formulations, the compositions may include sterile water for injection, sodium chloride, buffer systems such as phosphate or citrate buffers, or other components suitable for parenteral administration. The injectable formulations may be prepared as solutions, suspensions, or lyophilized powders for reconstitution prior to administration. The formulation may include stabilizers, antioxidants, or preservatives to maintain product quality and safety.

[0040] The compositions may be formulated as immediate-release or modified-release dosage forms depending on the desired pharmacokinetic profiles of the active ingredients. Modified- release formulations may include sustained-release, extended-release, or delayed-release characteristics that optimize the therapeutic benefit of the combination therapy. The release characteristics may be tailored to provide appropriate plasma concentrations of each active ingredient over the intended dosing interval.

[0041] The pharmaceutically acceptable excipients in the compositions may include binders such as hydroxypropyl cellulose or polyvinylpyrrolidone to provide tablet integrity. Disintegrants such as sodium starch glycolate or crospovidone or the like may be included to facilitate tablet2023-1007c breakdown and drug release. Lubricants such as magnesium stearate or stearic acid or the like may be included to prevent sticking during tablet compression.

[0042] The compositions may include solubilizing agents or surfactants to enhance the solubility and bioavailability of poorly soluble active ingredients. Solubilizing agents may include polyethylene glycol, polysorbate 80, or other suitable agents that improve drug dissolution. The solubilizing agents may be particularly beneficial when the combination includes multiple active ingredients with different solubility characteristics.

[0043] The compositions may be formulated to provide appropriate chemical and physical stability during storage. Stability considerations may include protection from light, moisture, or oxygen that could degrade sensitive active ingredients. The formulations may include antioxidants such as butylated hydroxytoluene or ascorbic acid to prevent oxidative degradation. Desiccants or moisture barriers may be incorporated into the packaging to maintain product stability.

[0044] The compounds may be formulated into various pharmaceutical dosage forms suitable for different routes of administration. The compositions may include pharmaceutically acceptable salts of the active compounds, which may provide improved solubility, stability, or bioavailability compared to the parent compounds. In aspects, the compositions containing these specific compounds may comprise pharmaceutically acceptable excipients that are selected based on the intended dosage form and route of administration. For example, for oral dosage forms, excipients may include microcrystalline cellulose, lactose, starch, croscarmellose sodium, magnesium stearate, or other components suitable for tablets or capsules. In a further example, for injectable formulations, excipients may include sterile water, saline, buffer systems, or other components suitable for parenteral administration. The pharmaceutically acceptable excipients used in compositions containing these specific compounds may be selected to maintain compound stability during storage and to facilitate proper drug release upon administration. The excipients may also be chosen to minimize adverse effects and to ensure compatibility with the active compound and other formulation components.

[0045] The compositions may be prepared using conventional pharmaceutical manufacturing techniques such as direct compression, wet granulation, or dry granulation for solid dosage forms. The manufacturing process may be designed to ensure uniform distribution of all active ingredients2023-1007C throughout the dosage form and to maintain the integrity of each component during processing. Quality control testing may be performed to verify the content, uniformity, and stability of each active ingredient in the finished combination product.Therapeutic Applications

[0046] In aspects, the composition may be effective for the treatment of a proliferative disorder. Proliferative disorders encompass various types of cancer and other conditions characterized by abnormal cell growth and division. Without intending to be limited by theory, the disclosed compounds, alone or in combination with other actives, may be administered to an individual in need thereof, to interfere with cellular pathways that regulate cell proliferation, thereby providing therapeutic benefit in treating such disorders.

[0047] In aspects, the disclosed compositions may be for used for treating a cancer in an individual in need thereof, for example, an individual having, or suspected of having a cancer is selected from an H / K / NRAS -driven disease, an HRAS-driven cancer, a KRAS-driven cancer, a NRAS -driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof. In aspects, the cancer is a solid tumor.

[0001] In aspects, the disclosed compositions may be used for treating lung cancer. In aspects, the disclosed compositions may be used for treating non-small cell lung cancer (NSCLC). In aspects, the disclosed compositions may be used for treating lung adenocarcinoma, a specific subtype of non-small cell lung cancer.

[0002] In aspects, the disclosed compositions may be used for treating Ewing Sarcoma. Ewing Sarcoma represents a rare but aggressive form of bone and soft tissue cancer that primarily affects children and young adults.

[0003] In aspects, the disclosed compositions may be used for treating a hyperactivated H / K / NRAS -driven disease. H / K / NRAS refers to the family of RAS proteins including HRAS, KRAS, and NRAS, which are frequently mutated in human cancers.2023-1007c

[0004] Tn aspects, the disclosed compositions may be used for treating breast cancer, including breast invasive ductal carcinoma. In aspects, the disclosed compositions may be used for treating triple-negative breast cancer (TNBC) and hormone-resistant triple negative breast cancer.

[0005] In aspects, the disclosed compositions may be used for treating pancreatic cancer. In aspects, the disclosed compositions may be used for treating pancreatic cancer driven by mutated KRAS.

[0006] In aspects, the disclosed compositions may be used for treating colorectal cancer. In aspects, the disclosed compositions may be used for treating colorectal cancer driven by mutated KRAS.

[0048] In aspects, the disclosed compositions may be used for treating leukemia. In aspects, the disclosed compositions may be for used for treating B-cell acute lymphoblastic leukemia (B- ALL). In aspects, the disclosed compositions may be for used for treating a KRAS-driven B-cell acute lymphoblastic leukemia. In aspects, the disclosed compositions may be used for treating relapsed or recurrent forms of KRAS-driven B-ALL, which may be particularly challenging to treat with conventional therapies. KRAS-driven B-ALL represents a subset of acute lymphoblastic leukemia cases where mutations in the KRAS gene contribute to the malignant transformation and proliferation of B-cell precursors. In aspects, the disclosed compositions may be used for treating lung cancer. In aspects, the disclosed compositions may be used for treating Ewing Sarcoma. In aspects, the disclosed compositions may be used for treating a hyperactivated H / K / NRAS -driven disease.

[0007] In aspects, the disclosed compositions may be used for treating a proliferative disorder, such as a cancer, characterized by the presence of one, or more than one, KRAS mutant. In aspects, the disclosed compositions may be used for treating a disease state characterized by a KRAS G12V mutant in addition to other KRAS mutants. In aspects, the disclosed compositions may be used for treating a proliferative disorder characterized by a KRAS G12V mutant. In aspects, the disclosed compositions may be used for treating a cancer characterized by a KRAS G12V mutant.Methods of Treatment

[0049] In one aspect, a method of treating a proliferative disorder, such as a cancer, is provided. In aspects, the method comprises administering a therapeutically effective amount of a2023-1007C compound of Table 1 as described herein, to an individual in need thereof. For example, in aspects, the individual has, or is suspected of having, a cancer selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof. In further aspects, the cancer is a solid tumor. In aspects, the individual has, or is suspected of having, an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer. In aspects, the individual has, or is suspected of having, Ewing sarcoma. In aspects, the individual has, or is suspected of having, B-cell acute lymphoblastic leukemia. In aspects, the individual has, or is suspected of having, leukemia. In aspects, the individual has, or is suspected of having, lung cancer. In aspects, the individual has, or is suspected of having, non-small cell lung cancer (NSCLC). In aspects, the individual has, or is suspected of having, a solid tumor. In aspects, the individual has, or is suspected of having, breast cancer. In aspects, the individual has, or is suspected of having, triple-negative breast cancer (TNBC). In aspects, the individual has, or is suspected of having, hormone-resistant triple negative breast cancer. In aspects, the individual has, or is suspected of having, a cancer characterized by one or more mutations selected from a KRAS- G13D oncogenic mutation, a CHEK1 mutation, and / or a STAT3 mutation. In aspects, the individual has, or is suspected of having, a cancer characterized by one or more mutations selected from KRAS oncogenic mutations in addition to other mutations in other genes such as BCOR, CCT6B, CHEK1 , MET, PRKDC, PTCHI, RAD50, RELN, STAT3, STAT5B, TET2, and / or WDR90.

[0050] In one aspect, the method comprises administering a composition comprising Compound 3-007 to the individual. In one aspect, the method comprises administering a composition consisting of, or consisting essentially of, Compound 3-007 to the individual.

[0051] In one aspect, the method comprises administering a composition comprising Compound 3-006 to the individual. In one aspect, the method comprises administering a composition consisting of, or consisting essentially of, Compound 3-006 to the individual.

[0052] In aspects, the administration is carried out over a period of about one day, or about one week, or about two weeks, or about three weeks, or about one month, or for more than one2023-1007C month. Tn a further aspect, the administration is carried out for a time sufficient to achieve a therapeutic benefit, such as stabilization of disease, reduction in tumor size, delayed progression, or improvement in clinical symptoms.

[0053] In one aspect, a dose of from about 1 mg / kg to about 10 mg / kg is administered.

[0054] The administration may be carried out via any method known in the art. Exemplary routes of administration are described herein, and include, for example, a route selected from oral, intravenous, subcutaneous, intramuscular, pulmonary (inhalation), topical, transdermal, intranasal, ophthalmic, buccal, epidural, intrathecal, and combinations thereof.Methods of Treatment - Combination Therapy with KRAS G12C Inhibitors

[0055] In one aspect, the disclosed methods comprise administering a combination or sequential treatment utilizing a KRAS G12C inhibitor in combination with a compound of Table 1 for treatment of a proliferative disorder such as a cancer. In one aspect, the method comprises the combination or sequential treatment to an individual having, or suspected of having a proliferative disorder selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS- driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, nonsmall cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof.

[0056] In this aspect, the method comprises administering a compound of Table 1 and a KRAS G12C inhibitor to an individual in need thereof. For example, in this aspect, both a compound of Table 1 and a KRAS G12C inhibitor are administered to an individual having, or suspected of having, a proliferative disorder such as a cancer as described herein. In one aspect, the administration is simultaneous. In one aspect, the administration is sequential. Administration is carried out until an improvement in the disease state is observed. Such improvement may comprise a cessation of cancer cell proliferation, reduction in tumor volume, reduction in metastatic spread, partial or complete tumor regression, stabilization of disease, or improvement in clinical parameters indicative of reduced disease activity.

[0057] In one aspect, the novel compound(s) (i.e., those of Table 1) described herein may be administered in a sequential treatment regimen with a KRAS G12C inhibitor to provide enhanced2023-1007c therapeutic efficacy in treating the proliferative disorder. This sequential approach may involve administering a novel compound(s) (i.e., one or more of Table 1, e.g., Compound 3-007 and / or Compound 3-006), followed by administration of a KRAS G12C inhibitor in a two-stage treatment protocol that may extend patient survival beyond what may be achieved with either agent alone. The timing of the sequential treatment regimen may be optimized to maximize therapeutic benefit. Administration of the KRAS G12C inhibitor may begin before, during, or after the treatment period of the first active. In some cases, the administration of the KRAS G12C inhibitor may be such that an overlap period occurs in which both the first and second active are administered simultaneously. Alternatively, the administration of the KRAS G12C inhibitor may be such that an overlap period does not occur such that the novel compound(s) of Table 1 (e.g., Compound 3- 007 and / or Compound 3-006) and the KRAS G12C inhibitor are not administered simultaneously whatsoever.

[0058] In one aspect, the compound of Table 1 used in conjunction with the KRAS G12C inhibitor is Compound 3-007. In aspects the KRAS G12C inhibitor used in conjunction with the compound of Table 1 is selected from sotorasib, adagrasib, divarasib, MK 1084, and combinations thereof. In aspects, the KRAS G12C inhibitor used in conjunction with the compound of Table 1 is sotorasib. In further aspects, the combination comprises, consists of, or consists essentially of Compound 3-007 and sotorasib.Methods of Treatment - Combination Therapy with MEK Inhibitors

[0059] In one aspect, the disclosed methods comprise administering a combination or sequential treatment utilizing a MEK inhibitor in combination with a compound of Table 1 for treatment of a proliferative disorder such as a cancer. In one aspect, the method comprises the combination or sequential treatment to an individual having, or suspected of having a proliferative disorder selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone- resistant triple negative breast cancer, and combinations thereof.

[0060] In this aspect, the method comprises administering a compound of Table 1 and a MEK inhibitor to an individual in need thereof. For example, in this aspect, both a compound of Table2023-1007c1 and a MEK inhibitor are administered to an individual having, or suspected of having, a proliferative disorder such as a cancer as described herein. In one aspect, the administration is simultaneous. In one aspect, the administration is sequential. Administration is carried out until an improvement in the disease state is observed. Such improvement may comprise a cessation of cancer cell proliferation, reduction in tumor volume, reduction in metastatic spread, partial or complete tumor regression, stabilization of disease, or improvement in clinical parameters indicative of reduced disease activity.

[0061] In one aspect, the novel compound(s) (i.e„ those of Table 1) described herein may be administered in a sequential treatment regimen with a MEK inhibitor to provide enhanced therapeutic efficacy in treating the proliferative disorder. This sequential approach may involve administering a novel compound(s) (i.e., one or more of Table 1, e.g., Compound 3-007 and / or Compound 3-006), followed by administration of a MEK inhibitor in a two-stage treatment protocol that may extend patient survival beyond what may be achieved with either agent alone. The timing of the sequential treatment regimen may be optimized to maximize therapeutic benefit. Administration of the MEK inhibitor may begin before, during, or after the treatment period of the first active. In some cases, the administration of the MEK inhibitor may be such that an overlap period occurs in which both the first and second active are administered simultaneously. Alternatively, the administration of the MEK inhibitor may be such that an overlap period does not occur such that the novel compound(s) of Table 1 (e.g., Compound 3-007 and / or Compound 3-006) and the MEK inhibitor are not administered simultaneously whatsoever.

[0062] In one aspect, the compound of Table 1 used in conjunction with the MEK inhibitor is Compound 3-007. In aspects the MEK inhibitor used in conjunction with the compound of Table 1 is selected from trametinib. cobimetinib, binimetinib, selumetinib, mirdametinib, PD 0325901, TAK 733, and combinations thereof. In aspects, the MEK inhibitor used in conjunction with the compound of Table 1 is trametinib. In further aspects, the combination comprises, consists of, or consists essentially of Compound 3-007 and trametinib.2023-1007CMethods of Treatment - Combination Therapy with a Selective Estrogen Receptor Degrader (SERD)

[0063] In one aspect, the disclosed methods comprise administering a combination or sequential treatment utilizing a Selective Estrogen Receptor Degrader (SERD) in combination with a compound of Table 1 for treatment of a proliferative disorder such as a cancer. In one aspect, the method comprises the combination or sequential treatment to an individual having, or suspected of having a proliferative disorder selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof.

[0064] In this aspect, the method comprises administering a compound of Table 1 and a SERD to an individual in need thereof. For example, in this aspect, both a compound of Table 1 and a SERD are administered to an individual having, or suspected of having, a proliferative disorder such as a cancer as described herein. In one aspect, the administration is simultaneous. In one aspect, the administration is sequential. Administration is carried out until an improvement in the disease state is observed. Such improvement may comprise a cessation of cancer cell proliferation, reduction in tumor volume, reduction in metastatic spread, partial or complete tumor regression, stabilization of disease, or improvement in clinical parameters indicative of reduced disease activity.

[0065] In one aspect, the novel compound(s) (i.e., those of Table 1) described herein may be administered in a sequential treatment regimen with a SERD to provide enhanced therapeutic efficacy in treating the proliferative disorder. This sequential approach may involve administering a novel compound(s) (i.e., one or more of Table 1, e.g., Compound 3-007 and / or Compound 3- 006), followed by administration of a SERD in a two-stage treatment protocol that may extend patient survival beyond what may be achieved with either agent alone. The timing of the sequential treatment regimen may be optimized to maximize therapeutic benefit. Administration of the SERD may begin before, during, or after the treatment period of the first active. In some cases, the administration of the SERD may be such that an overlap period occurs in which both the first and second active are administered simultaneously. Alternatively, the administration of the SERD may2023-1007C be such that an overlap period does not occur such that the novel compound(s) of Table 1 (e.g., Compound 3-007 and / or Compound 3-006) and the SERD are not administered simultaneously whatsoever.

[0066] In one aspect, the compound of Table 1 used in conjunction with the SERD is Compound 3-007. In aspects the SERD used in conjunction with the compound of Table 1 is selected from fulvestrant, elacestrant, imlunestrant, camizestrant, giredestrant, amcenestrant, bexirestrant, rintodestrant, and combinations thereof. In aspects, the SERD used in conjunction with the compound of Table 1 is fulvestrant. In further aspects, the combination comprises, consists of, or consists essentially of Compound 3-007 and fulvestrant.

[0067] In one aspect, a method of treating a cancer is provided comprising administration of a compound of Table 1, in which a MEK inhibitor is not administered to the individual. For example, in such aspects, the method comprises administering a composition as described herein to an individual in need thereof without concurrent administration of a MEK inhibitor. In aspects, the cancer is selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone- resistant triple negative breast cancer, and combinations thereof. In aspects, the MEK inhibitor that is excluded from the treatment includes a MEK inhibitor selected from trametinib (Mekinist), cobimetinib (Cotellic), binimetinib (Mektovi), selumetinib (Koselugo), pimasertib, refametinib, and combinations thereof. In one aspect the MEK inhibitor that is excluded is trametinib.

[0068] In one aspect, a method of treating a cancer is provided in which the method comprises administering a composition s described herein and a KRAS G12C inhibitor, to an individual in need thereof. In aspects, the cancer is selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof. In aspects, the KRAS G12C inhibitor may be one or both of sotorasib and adagrasib. In aspects, the KRAS G12C inhibitor may be sotorasib.2023-1007cMethods of Treatment - Route of Administration

[0069] The method of administering the composition may involve various routes of administration depending on the specific formulation and clinical requirements. Administration may be selected from oral, intravenous, subcutaneous, intramuscular, pulmonary (inhalation), topical, transdermal, intranasal, ophthalmic, buccal, epidural, intrathecal, and combinations thereof. The choice of administration route may depend on factors such as the specific cancer type being treated, the patient's condition, the desired pharmacokinetic profile, and the formulation characteristics of the composition.

[0070] The methods may involve combinations of different administration routes to optimize therapeutic outcomes. Combination administration approaches may include sequential use of different routes during different phases of treatment or simultaneous use of multiple routes to achieve both local and systemic therapeutic effects. The combination approach may allow for tailored treatment regimens that address the specific anatomical distribution and characteristics of each patient’s cancer. The selection of administration routes may be individualized based on patient-specific factors such as age, performance status, comorbidities, and previous treatment history. Pediatric patients may require specialized formulations and administration techniques that account for developmental differences in drug absorption, distribution, and metabolism. Elderly patients may benefit from administration routes that minimize pill burden or provide simplified dosing regimens. The administration methods may be modified during the course of treatment based on patient response, tolerability, or changes in clinical condition. Treatment modifications may include switching between different administration routes, adjusting dosing frequencies, or combining multiple routes to optimize therapeutic benefit while maintaining acceptable tolerability profiles.DEFINITIONS

[0071] Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art. In case of conflict, the present document, including definitions, will control. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein may be used in practice or testing of the present invention. All publications, patent applications, patents and other references mentioned2023-1007c herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. The methods may comprise, consist of, or consist essentially of the elements of the compositions and / or methods as described herein, as well as any additional or optional element described herein or otherwise useful in the treatment of a proliferative disorder, such as a cancer via administration of one or more of the compounds or compositions here.

[0072] As used herein and in the appended claims, the singular forms “a,” “and,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a method” includes a plurality of such methods and reference to “a dose” includes reference to one or more doses and equivalents thereof known to those skilled in the art, and so forth.

[0073] The term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” may mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” may mean a range of up to 20%, or up to 10%, or up to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term may mean within an order of magnitude, preferably within 5 -fold, and more preferably within 2- fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term “about” meaning within an acceptable error range for the particular value should be assumed.

[0074] As used herein, the term “effective amount” means the amount of one or more active components that is sufficient to show a desired effect. This includes both therapeutic and prophylactic effects. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

[0075] The terms “individual,” “host,” “subject,” and “patient” are used interchangeably to refer to an animal that is the object of treatment, observation and / or experiment. Generally, the term refers to a human patient, but the methods and compositions may be equally applicable to2023-1007c non-human subjects such as other mammals. Tn some aspects, the terms refer to humans. In further aspects, the terms may refer to children.EXAMPLES

[0076] The following non-limiting examples are provided to further illustrate embodiments of the invention disclosed herein. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent approaches that have been found to function well in the practice of the invention, and thus may be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes may be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.Example 1

[0077] Applicant has found that the efficacy of Compound 3-007 is not restricted to one specific KRAS mutant but works in the context of several mutants. Compound 3-007 and other analogs can be used to treat hyperactivated H / K / NRAS-driven cancers regardless of the nature of the lesion. This efficacy of Compound 3-007 against models of oncogenic RAS stems from RAC activation for RAS transformation. Screening of Compound 3-007 against cell lines representative of human cancers shows that it is efficacious against various cancers including Ewing Sarcoma, lung adenocarcinoma, and breast invasive ductal carcinoma. The ability of Compound 3-007 to decrease the survival of 868 cancer cell lines passing quality control (QC) was tested. These cell lines are representative of most human cancers. Benchmark compounds were tested in parallel to ensure high data quality. Viability was recorded in a dose response manner at 8 concentrations starting at 3 pM down to 14 nM. For each cell line, IC50, EC50 and AUC (area under the curve) were computed. Plot of the AUC function of cancer lineage subtype (see FIGS. 15A-15B) reveals that cell lines of the Ewing Sarcoma, breast invasive ductal carcinoma, and lung adenoma lineage are most sensitive to compound 3-007. Accordingly, Compound 3-007 alone or in combination with standard of care should greatly improve the outcome of cancer patients.2023-1007CExample 2

[0078] Analogs of IODVA1B were synthesized by changing the nature of the -R group on the central imidazole, as shown in Table 1 and according to the scheme in FIG. 2. The Z01 group yielded Compound 3-006 and the Z02 group yielded Compound 3-007. The activity of the synthesized analogs was tested in a dose dependent manner on cancer cells including MCF7 (ER+) and MDA-MB-231 (TNBC) breast cancer cells. Compound concentrations that resulted in growth inhibition at 50% (GKOs) are listed in Table 1. Compiled data show that compounds Compound 3-006 and Compound 3-007 are among the most efficacious analogs. Better solubility was observed with Compound 3-007 as compared to Compound 3-006. In general, GI50 values obtained for Compound 3-006 and Compound 3-007 were at least 10 times lower than those obtained with IODVA1.

[0079] As depicted in FIG. 3, to test if Compound 3-007 binds to VAV3, a biotinylated form of Compound 3-007 was conjugated to neutravidin beads. The beads were incubated for one hour with recombinant VAV3 purified from E. coli at 0.1 or 0.5 pM. Beads were washed 3 times with binding buffer (20 mM Tris-HCl pH = 8, 150 mM NaCl, 1 mM DTT) and incubated with 1ODVA1 or 3-007 at 10 pM for one hour. Beads were then boiled in SDS-Laemmeli buffer and immunoblotted for VAV3. Band intensity was quantified in Image!. As shown in the immunoblot (FIG. 4), Compound 3-007 successfully elutes VAV3 from the beads, suggesting binding to VAV3.

[0080] The ability of Compound 3-007 to decrease the survival of Ba / F3 leukemic cells expressing the pl90-BCR-ABL oncogene was tested. FIG. 5 shows that Compound 3-007 decreases survival of these cells with a GKO of 6.8 nM. This value is about 30 times lower than that for IODVA1 for the same cells and under the same conditions (See, e.g., Hegde et al., 2022 S., Gasilina A., Wunderlich M., et al. Leukemia Mar;36(3):637-647 (2022) - PMID 34711926). To test if Compound 3-007 targets the RAC-activator VAV3, full-length and the dominant active form of VAV3 (ACH-VAV3) in the pl90-BCR-ABL expressing Ba / F3 cells and determined the GKO of Compound 3-007 for these cells. The GKO is increased 8 to 9 fold upon expression of VAV3 proteins, suggesting that Compound 3-007 targes VAV3 or a protein overexpressed / activated by VAV3.2023-1007C

[0081] To test the efficacy of the new analogs in models of oncogenic KRAS-driven cancer, whether oncogenic KRAS activated VAV3 was first tested. Ba / F3 leukemic cell lines stably expressing HA-tagged wild-type or the G12C mutant of KRAS were generated. Cells were grown, lysed, and immunoblotted for pVAV3, VAV3, and HA-tag to check the expression of exogenous KRAS, and pan-RAS to check that KRAS was not overexpressed. GAPDH was used as a loading control. (See FIG. 6. top panel) Compared to Ba / F3 cells, expression of wild-type or G12C mutant of KRAS activates VAV3 as shown by the increased level of pVAV3. Together, these data suggest that oncogenic KRAS activates VAV3, likely through the activation of SRC-family kinases. (See FIG 6, bottom panel)

[0082] Applicant found that Compound 3-007 increases the survival of a KRAS G12C-driven leukemia and synergizes with trametinib. The G12C mutant of KRAS was used in an in vivo model to test the efficacy of Compound 3-007 because this mutant is sensitive to sotorasib, the recently FDA-approved drug that is KRAS G12C specific. Balb / C mice were transplanted with 500,000 Ba / F3 cells expressing KRAS G12C. Once leukemia was fully developed, mice were divided into 7 groups (6 mice each) and treated for 41 days (day 17-59, grey area) with Compound 3-007, trametinib, sotorasib, and their combinations (FIG. 7A). At the end of the treatment, mice were observed in their cages. Drugs at the following concentrations: 3-007 (1 mM), sotorasib (0.25 mM), trametinib (0.25 mM), were delivered in subcutaneous osmotic pumps. Mice survival is shown in FIG. 7A. The probability of survival shows that as monotherapy, Compound 3-007 is superior to sotorasib and trametinib and that the Compound 3-007 / trametinib combination is the most efficacious treatment. Compound 3-007 treatment increased leukemic mice survival by 53 days following treatment withdrawal. Percentage of leukemic cells (F4 / 80+ and B220+) in peripheral blood are shown in FIG. 7B. The combination of Compound 3-007 and trametinib decreases the leukemic burden most efficiently. Together, these data show that Compound 3-007 synergizes with the MEK-inhibitor trametinib to treat KRAS-driven leukemia.Applicant found that Compound 3-007 increases the survival of a relapsed / refractory PDX model of oncogenic KRAS-B-ALL. To test the efficacy of Compound 3-007 on patient-derived xenograft models. 1,000,000 leukemic cells from PDX 2019-163 were transplanted into sublethally irradiated NSG mice until leukemia was established. PDX 2019-163 is characterized by KRAS- G13D oncogenic mutation and several genetic alterations including CHEK1 and STAT3 mutations2023-1007C(BCOR QI 119R, CCT6B D491G, CHEK1 T153I, MET G654R, PRKDC P3676S, PTCHI E44G and S827G, RAD50 Q199H, RELN F1898V, STAT3 A766T, STAT5B A729S, TET2 P1802L, WDR90 P1727fs*87. Mice were divided into 7 treatment groups, 6 mice each. Treatment included saline vehicle control, the SOS1 inhibitor BL3406 (4 mM), trametinib (0.5 mM), Compound 3- 007 (1 mM), and the various combinations as shown in FIG. 8 A. Drugs were administered in subcutaneous osmotic pumps. Treatment started on day 35 and ended on day 78 after which the mice were observed in their cages. The survival curve and the leukemic burden count shown in FIG. 8A, and 8B, respectively show that as a monotherapy, Compound 3-007 is more efficacious than trametinib and that Compound 3-007 synergizes with trametinib to efficiently prolong mice survival even following drug withdrawal.

[0083] Compound 3-007 targets the RAC / PAK1 pathway in vivo. To validate the mechanism of action of Compound 3-007 in vivo, the ability of Compound 3-007, trametinib, and of Compound 3-007 / trametinib combination treatments at decreasing the activity of the RAC / PAK1 and MAPK pathways in the leukemia of the previously treated mice were tested (FIG. -A). Human leukemic cells obtained from the bone marrow of the treated mice at the time of the humanly sacking were subjected to phospho-flow analysis. As shown in FIG. 9, trametinib significantly decreases levels of phospho-ERK (pERK), pJNK, and STAT3 / STAT5 but not levels of pPAKl. Compound 3-007 significantly decreases levels pPAKl and pSTAT3 but not pERK or pSTAT5. The drug combination on the other hand significantly decreases levels of all effectors. Similarly, levels of phosphorylated-ERK (pERK), the KRAS -downstream effector from the human leukemic cells purified from the bone marrow of the treated mice were quantified by immunoblotting. FIG. -C shows that pERK was high at the start of the treatment, decreases at the treatment end in the trametinib and combination groups only, and increases again at the relapse. Taken together, the data show that Compound 3-007 targets the VAV3 / RAC / PAK1 but not the RAS / ERK pathway and synergizes with trametinib (FIG. 10).

[0084] Compound 3-007 targets cellular models of KRAS-driven lung cancer. To test if Compound 3-007 is also efficacious in models of oncogenic KRAS-driven solid tumors, its efficacy in cellular models of lung cancer was tested. The ability of Compound 3-007 to decrease the survival of the H441 and H292 cell lines was tested. H441 expresses KRASG12V while H292 is wildtype for EGFR and KRAS. FIG. 11 shows that Compound 3-007 decreases the survival of2023-1007cH441 and H292 with growth inhibitory et 50% of 20 and 300 nM, respectively. Taken together, the data demonstrate that Compound 3-007 is efficacious in models of KRAS-driven solid tumors and shows specificity to oncogenic KRAS.

[0085] Compound 3-007 kinase Inhibitory Activity. Compound 3-007 has two pyridine groups attached to one imidazole group carbon. Pyridine is among the most common scaffolds found in kinase inhibitors (Xing et al., 2014) and is found in several potent inhibitors of FLT3, Aurora, ROCK, AKT, and other kinases (Bavetsias et al., 2012; Green et al., 2015; Woods et al., 2006) suggesting that 3-007 might have kinase inhibitory activity. Kinase inhibitory activity of Compound 3-007 was tested at a single concentration of 500 nM using the SelectScreen Services at Life Technology Co. (ThermoFisher Scientific). 485 wild-type and mutant kinases were tested in duplicate and the percentage inhibition was plotted for both assays (FIG. 12). For each kinase, the two readouts were plotted against each other (circles). This screen shows that at 500 nM, Compound 3-007 reduces the activity of MELK, MEK1, MAPK12, PRKCD, NEK8. and CAMK1 by -20% and increases the activity of MYLK2 by -40%. Kinases inhibited by -20% in both readouts are highlighted. The light grey line corresponds to Readout 1 = Readout2. Taken together, it is concluded that Compound 3-007 is not a kinase inhibitor.

[0086] Compound 3-007 activity against cancer cell lines. The ability of Compound 3-007 to decrease the survival of 868 cancer cell lines passing quality control (QC) was tested. The cell lines are representative of most human cancers. Benchmark compounds were tested in parallel to ensure high data quality. Viability was recorded in a dose response manner at 8 concentrations starting at 3 pM down to 14 nM. For each cell line, IC50, EC50 and AUC (area under the curve) were computed. Plot of the AUC function of cancer lineage subtype (NOT SHOWN) reveals that cell lines of the Ewing Sarcoma, breast invasive ductal carcinoma, and lung adenoma lineage are most sensitive to Compound 3-007. For each lineage, an effect size, the difference between that lineage and all others, and p-values based on a t-test, were calculated. A plot of the q-values, a corrected significance value accounting for false discovery rate computed from p-values using the Benjamini-Hochberg algorithm function of the effect size is shown in FIG.13. FIG. 13 shows that Ewing Sarcoma is the most sensitive lineage to Compound 3-007.2023-1007C

[0087] Compound 3-007 analogs. Since Compound 3-007 shows efficacy in vivo and lack of toxicity to mice, analogs of this compound were synthesized and tested against MCF7 and MDA- MB-231 breast cancer cell lines. Viability assays were done in triplicates and averaged IC50 were calculated. The screening resulted in 5 novel compounds with IC50s between 25 and 100 nM (FIG. 1 and Table 2). Interestingly, these novel compounds had higher solubility than Compound 3-007.

[0088] Table 2. Results of evaluating Compound 3-007 and analogs of Compound 3-007 tested. The efficacy of Compound 3-007 or of its analogs was tested against MCF7 and MDA- MB-231 triple negative breast cancer cells. The most efficacious compounds with their IC50 are reported in this table.2023-1007C

[0089] In sum, novel chemical entities with biological activities were developed by attaching various chemical groups to the central imidazole of IODVA1B, see Table 1. At least one analog, i.e. Compound 3-007 is efficacious in cellular and in vivo models of KRAS-driven B-cell acute lymphoblastic leukemia (B-ALL) including a relap se / recurrent PDX model with acceptable toxicity. The data show that Compound 3-007 ’s efficacy is not restricted to one specific KRAS mutant but works in the context of several mutants. It is believed that Compound 3-007 and other analogs can be used to treat hyperactivated H / K / NRAS-driven cancers regardless of the nature of the lesion. This efficacy of Compound 3-007 against models of oncogenic RAS stems from the RAC activation for RAS transformation. The data indicate that Compound 3-007 is superior to FDA-approved and standard of care sotorasib and trametinib in relapsed / recurrent PDX models of leukemia and synergizes with trametinib. Thus, the data support the use of Compound 3-007 alone or in combination with standard of care for improving the outcome of cancer patients.

[0090] Screening of Compound 3-007 against cell lines representative of human cancers shows that it is most efficacious against Ewing Sarcoma, lung adenocarcinoma, and breast invasive ductal carcinoma, but which may also be useful for treatment of high-risk leukemia, lung cancer (particularly NSCLC), and triple negative breast cancer (TNBC). Although Compound 3-007 is not tested in vivo models of solid tumors, its efficacy in cellular models of breast cancer, particularly hormone treatment resistant triple negative breast cancer, and lung cancer suggest that it will be efficacious in in vivo models of these cancers. Analog screening of Compound 3-007 resulted in additional compounds with comparable efficacy.

[0091] Compound 3-007 administration followed by fulvestrant as a novel treatment for KRAS-driven leukemia. NSG mice were engrafted with one million cells from PDX 2014-11, a R / R with KRASG12V from an 16y / o male patient with disease relapse after initial treatment. When leukemic burden reached -15%, mice were randomly divided into 3 groups (3 male + 32023-1007c female) each and treated with vehicle control, 3-007 (days 28-to-56), and 3-007 (days 28-to-56, indicated by Tl) followed by fulvestrant (day 51 to 105, indicated by T2). fulvestrant was IP administered at 25 mg / kg once a week. Kaplan-Meier plots were generated in GraphPad. FIG. 14, panel A shows the survival curves of KRAS-driven B-ALL in response to vehicle, 3-007, and 3- 007 / T1 + Fulvestrant / T2.

[0092] Referring again to FIG. 8, panel B, the above was carried out but with cells from PDX 2019-163, a relapse B-ALL with KRASG13D from an 8y / o female patient. Fulvestrant was IP administered at 25 mg / kg once a week. Kaplan-Meier plots were generated in GraphPad. FIG. 14, panel B shows the survival curves of KRAS-driven B-ALL in response to vehicle, 3-007, and 3- 007 / T1 + Fulvestrant / T2.

[0093] In both PDX models, Compound 3-007 increased survival of KRAS leukemic mice. However, mice eventually succumbed after treatment withdrawal. Fulvestrant administration post Compound 3-007 further increase mice survival by more than 70 days. The increase in leukemic mice survival was independent of the KRAS mutation or the sex of the patient and did not require a MAPK-inhibitor (e.g. trametinib or vemurafenib). A MAPK-inhibitor to IODVA1 is expected to increase the survival of KRAS B-ALL patients. As oncogenic KRAS is the driver of several human cancers (e.g. pancreatic, colorectal, lung), based on the data, it is predicted that the Compound 3- 007 / fulvestrant combination described is also useful for the treatment of solid tumors with mutated KRAS.Exemplary Combinations

[0094] The following examples relate to various non-exhaustive ways in which the teachings herein may be combined or applied. It should be understood that the following examples are not intended to restrict the coverage of any claims that may be presented at any time in this application or in subsequent filings of this application. No disclaimer is intended. The following examples are being provided for nothing more than merely illustrative purposes. It is contemplated that the various teachings herein may be arranged and applied in numerous other ways. It is also contemplated that some variations may omit certain features referred to in the below examples. Therefore, none of the aspects or features referred to below should be deemed critical unless otherwise explicitly indicated as such at a later date by the inventors or by a successor in interest2023-1007C to the inventors. If any claims are presented in this application or in subsequent filings related to this application that include additional features beyond those referred to below, those additional features shall not be presumed to have been added for any reason relating to patentability.

[0095] Example 1

[0096] A composition comprisingor a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0097] Example 2

[0098] The composition of example 1, wherein R = H, or a straight chain or branched alkyl group having 1-8 carbon atoms, or R = CH2CF3.

[0099] Example 3

[0100] The composition of example 2, wherein the alkyl group is a methyl group.

[0101] Example 4

[0102] The composition of example 2 wherein the alkyl group is an ethyl group.

[0103] Example 5

[0104] The composition of example 1, wherein R — -CH2-R , and wherein R is a C3-C6 cycloalkane, a phenyl group, a halogen-substituted phenyl group, a thiophene, a pyridine, a 1,3- dioxolane, or a tetrahydropyran.2023-1007C

[0105] Example 6

[0106] The composition of example 5. wherein the halogen is F, Cl or Br.

[0107] Example 7

[0108] The composition of example 1, wherein R = CH2-CH2-R2and wherein R2is a C3-C6 cycloalkane, a phenyl group, a halogen-substituted phenyl group, a thiophene, a pyridine, a 1,3- dioxolane, or a tetrahydropyran.

[0109] Example 8

[0110] The composition of example 7, wherein the halogen is F, Cl or Br.

[0111] Example 9

[0112] The composition of example 1, wherein R = CH2-CH2-CH2F.

[0113] Example 10

[0114] The composition of any preceding example wherein R is not H.

[0115] Example 11

[0116] A composition comprising:at least one halogen, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0117] Example 122023-1007C

[0118] A composition comprising:least one halogen or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0119] Example 13

[0120] A composition comprising a compound selected from2023-1007Cor a pharmaceutically acceptable salt thereof, and combinations thereof; and a pharmaceutically acceptable excipient.

[0121] Example 14

[0122] The composition of any preceding example, wherein said composition is effective for the treatment of a proliferative disorder.

[0123] Example 15

[0124] The composition of any of examples 1-13, for use in treating KRAS-driven B-cell acute lymphoblastic leukemia.

[0125] Example 16

[0126] The composition of any of examples 1-13, for use in treatment of leukemia.

[0127] Example 172023-1007C

[0128] The composition of any of examples 1-13, for use in treatment of lung cancer.

[0129] Example 18

[0130] The composition of any of examples 1-13, for use in treatment of Ewing Sarcoma.

[0131] Example 19

[0132] The composition of any of examples 1-13, wherein said composition is used to treat a hyperactivated H / K / NRAS -driven disease.

[0133] Example 20

[0134] A method of treating a cancer selected from an H / K / NRAS -driven disease, an HRAS- driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof, comprising administering a composition according to any of examples 1-13 to an individual in need thereof.

[0135] Example 21

[0136] A method of treating a cancer selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof, comprising administering a composition according to any of examples 1-13 and a MEK inhibitor, to an individual in need thereof.

[0137] Example 22

[0138] The method of example 21, wherein said MEK inhibitor is selected from trametinib (Mekinist). cobimetinib (Cotellic), binimetinib (Mektovi), selumetinib (Koselugo), pimasertib, refametinib, and combinations thereof.

[0139] Example 232023-1007C

[0140] The method of example 21 or 22, wherein said MEK inhibitor is trametinib

[0141] Example 24

[0142] A method of treating a cancer selected from an HRAS -driven cancer, a KRAS -driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof, comprising administering a composition according to any of examples 1-13 and a KRAS mutant inhibitor, to an individual in need thereof.

[0143] Example 25

[0144] A composition comprising the composition of any of examples 1-13, and one or both of a MEK inhibitor and a pan-RAS inhibitor.

[0145] Example 26

[0146] A method of treating a cancer selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC). hormone-resistant triple negative breast cancer, and combinations thereof, comprising administering a composition according to any of examples 1-13 and a Selective Estrogen Receptor Degrader (SERD), to an individual in need thereof.

[0147] Example 27

[0148] The method of example 26, wherein said SERD is selected from fulvestrant, elacestrant, imlunestrant, camizestrant, giredestrant, amcenestrant, bexirestrant, rintodestrant, and combinations thereof.

[0149] Example 28

[0150] The method of example 26 or 27, wherein said SERD is fulvestrant.

[0151] Example 292023-1007C

[0152] The method of any of examples 20-28, wherein said administration is selected from oral, intravenous, subcutaneous, intramuscular, pulmonary (inhalation), topical, transdermal, intranasal, ophthalmic, buccal, epidural, intrathecal, and combinations thereof.

[0153] Example 30

[0154] A method of treating a proliferative disorder in an individual in need thereof, comprising administering a first composition comprising Compound 3-007, or a pharmaceutically acceptable salt thereof, and a second composition comprising sotorasib, trametinib, fulvestrant, or a combination thereof.

[0155] Example 31

[0156] The method of example 30. wherein the combination of the first composition comprising Compound 3-007 and the second composition produces a synergistic therapeutic response in the individual.

[0157] Example 32

[0158] The method of example 30 or 31 wherein the proliferative disorder is a cancer.

[0159] Example 33

[0160] The method of any one of examples 30 to 32 wherein the proliferative disorder is a cancer selected from an HRAS -driven cancer, a KRAS -driven cancer, a NRAS -driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone- resistant triple negative breast cancer, and combinations thereof.

[0161] Example 34

[0162] A method of treating a proliferative disorder in an individual in need thereof, comprising administering a first composition comprising Compound 3-007, or a pharmaceutically acceptable salt thereof, and a second composition comprising Compound 3-007 and a second agent selected from sotorasib, trametinib, fulvestrant, or combinations thereof.2023-1007C

[0163] Example 35

[0164] The method of example 34 wherein the proliferative disorder is a cancer selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof

[0165] All percentages and ratios are calculated by weight unless otherwise indicated.

[0166] All percentages and ratios are calculated based on the total composition unless otherwise indicated.

[0167] It should be understood that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0168] The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values recited. Instead, unless otherwise specified, each such dimension is intended to mean both the recited value and a functionally equivalent range surrounding that value. For example, a dimension disclosed as “20 mm” is intended to mean “about 20 mm.”

[0169] Every document cited herein, including any cross referenced or related patent or application, is hereby incorporated herein by reference in its entirety unless expressly excluded or otherwise limited. All accessioned information (e.g., as identified by PUBMED, PUBCHEM, NCBI, UNIPROT, or EBI accession numbers) and publications in their entireties are incorporated into this disclosure by reference in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. The citation of any document is not an admission that it is prior art with respect to any invention disclosed or claimed herein or that it2023-1007C alone, or in any combination with any other reference or references, teaches, suggests or discloses any such invention. Further, to the extent that any meaning or definition of a term in this document conflicts with any meaning or definition of the same term in a document incorporated by reference, the meaning or definition assigned to that term in this document shall govern.

[0170] While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications may be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims

2023-1007cCLAIMSWhat is claimed is:

1. A composition comprising<img src='' class="img-anchor img-center" img-id="IMGF000039_0001" / >or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

2. The composition of claim 1, wherein R = H, or a straight chain or branched alkyl group having 1-8 carbon atoms, or R = CH2CF3.

3. The composition of claim 2, wherein the alkyl group is a methyl group.

4. The composition of claim 2 wherein the alkyl group is an ethyl group.

5. The composition of claim 1, wherein R = -CH2-R2, and wherein R2is a C3-C6 cycloalkane, a phenyl group, a halogen-substituted phenyl group, a thiophene, a pyridine, a 1,3-dioxolane, or a tetrahydropyran.

6. The composition of claim 5, wherein the halogen is F, Cl or Br.

7. The composition of claim 1, wherein R = CH2-CH2-R2and wherein R2is a C3-C6 cycloalkane, a phenyl group, a halogen-substituted phenyl group, a thiophene, a pyridine, a 1,3- dioxolane, or a tetrahydropyran.

8. The composition of claim 7, wherein the halogen is F, Cl or Br.

9. The composition of claim 1, wherein R = CH2-CH2-CH2F.

10. The composition of any preceding claim wherein R is not H.2023-1007C11. A composition comprising:wherein R is at least one halogen, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. A composition comprising:least one halogen or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. A composition comprising a compound selected from2023-1007cor a pharmaceutically acceptable salt thereof, and combinations thereof; and a pharmaceutically acceptable excipient.2023-1007c14. The composition of any preceding claim, wherein said composition is effective for the treatment of a proliferative disorder.

15. The composition of any of claims 1-13, for use in treating KRAS-driven B-cell acute lymphoblastic leukemia.

16. The composition of any of claims 1-13, for use in treatment of leukemia.

17. The composition of any of claims 1-13, for use in treatment of lung cancer.

18. The composition of any of claims 1-13, for use in treatment of Ewing Sarcoma.

19. The composition of any of claims 1-13, wherein said composition is used to treat a hyperactivated H / K / NRAS -driven disease.

20. A method of treating a cancer selected from an H / K / NRAS -driven disease, an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof, comprising administering a composition according to any of claims 1-13 to an individual in need thereof.

21. A method of treating a cancer selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof, comprising administering a composition according to any of claims 1-13 and a MEK inhibitor, to an individual in need thereof.

22. The method of claim 21, wherein said MEK inhibitor is selected from trametinib (Mekinist), cobimetinib, binimetinib, selumetinib, pimasertib, refametinib, and combinations thereof.

23. The method of claim 21 or 22, wherein said MEK inhibitor is trametinib24. A method of treating a cancer selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast2023-1007C cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof, comprising administering a composition according to any of claims 1-13 and a KRAS mutant inhibitor, to an individual in need thereof.

25. A composition comprising the composition of any of claims 1-13, and one or both of a MEK inhibitor and a pan-RAS inhibitor.

26. A method of treating a cancer selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS -driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof, comprising administering a composition according to any of claims 1-13 and a Selective Estrogen Receptor Degrader (SERD), to an individual in need thereof.

27. The method of claim 26, wherein said SERD is selected from fulvestrant, elacestrant, imlunestrant, camizestrant, giredestrant, amcenestrant, bexirestrant, rintodestrant, and combinations thereof.

28. The method of claim 26 or 27, wherein said SERD is fulvestrant.

29. The method of any of claims 20-28, wherein said administration is selected from oral, intravenous, subcutaneous, intramuscular, pulmonary (inhalation), topical, transdermal, intranasal, ophthalmic, buccal, epidural, intrathecal, and combinations thereof.

30. A method of treating a proliferative disorder in an individual in need thereof, comprising administering a first composition comprising Compound 3-007, or a pharmaceutically acceptable salt thereof, and a second composition comprising sotorasib, trametinib, fulvestrant, or a combination thereof.

31. The method of claim 30, wherein the combination of the first composition comprising Compound 3-007 and the second composition produces a synergistic therapeutic response in the individual.

32. The method of claim 30 or 31 wherein the proliferative disorder is a cancer.2023-1007c33. The method of any one of claims 30 to 32 wherein the proliferative disorder is a cancer selected from an HRAS-driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B- cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof.

34. A method of treating a proliferative disorder in an individual in need thereof, comprising administering a first composition comprising Compound 3-007, or a pharmaceutically acceptable salt thereof, and a second composition comprising Compound 3-007 and a second agent selected from sotorasib, trametinib, fulvestrant, or combinations thereof.

35. The method of claim 34 wherein the proliferative disorder is a cancer selected from an HRAS- driven cancer, a KRAS-driven cancer, a NRAS-driven cancer, Ewing sarcoma, B-cell acute lymphoblastic leukemia, leukemia, lung cancer, non-small cell lung cancer (NSCLC), solid tumor, breast cancer, triple-negative breast cancer (TNBC), hormone-resistant triple negative breast cancer, and combinations thereof

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