Synergistic therapies for treating cancer

Abstract

The present invention relates combination therapies for treating cancer, said therapies comprising a piperazine derivative and a chemotherapeutic and / or a targeted therapy agent, methods for their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds, especially for targeted therapy of hyperproliferative disorders, including benign hyperproliferative disorders, cancers and pre-cancerous conditions.

Description

[0001] SYNERGISTIC THERAPIES FOR TREATING CANCER

[0002] FIELD OF INVENTION

[0003]

[0001] The present invention provides combination therapies for treating cancer, said therapies comprising a piperazine derivative and a chemotherapeutic or targeted therapy agent, methods for their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds, especially for targeted therapy of hyperproliferative disorders, including benign hyperproliferative disorders, cancers and pre-cancerous conditions.

[0004] BACKGROUND OF THE INVENTION

[0005]

[0002] Cancer remains a significant global health challenge, with an estimated 10 million cancer deaths per year. Despite significant advancements in cancer treatment, the overall survival rate remains suboptimal, and there is an urgent need for novel therapeutic strategies to improve outcomes for cancer patients.

[0006]

[0003] Existing cancer therapies, including surgery, radiation therapy, and chemotherapy, often have limited efficacy and can cause severe side effects. Additionally, cancer cells have a remarkable ability to develop resistance to these treatments, rendering them ineffective over time. Therefore, the development of new cancer therapies that can overcome these limitations and provide more durable and effective treatment options is essential.

[0007]

[0004] The use of combination drug therapy in cancer treatment has emerged as a promising strategy to combat the heterogeneity and adaptability of cancer cells. By employing drugs with diverse mechanisms of action, combination therapy aims to enhance antitumor efficacy while mitigating the development of drug resistance.

[0008]

[0005] However, this approach comprises several challenges and potential drawbacks. First, the effectiveness of combination therapy is highly dependent on the selection of appropriate drug combinations. An extremely large number of therapeutically effective molecules have been proposed for cancer treatment, making a systematic experimentation of all possible combinations virtually impossible. Most combinations of drugs show only an additive effect, and in some cases even the individual effect of each of the drugs is hampered by their combination. Furthermore, combinations of drugs have potential for increased toxicity. When multiple drugs are administered simultaneously, the cumulative effect on normal tissues can be exacerbated, leading to adverse side effects that may compromise the patient's quality of life. Thus, the identification of synergistic drug pairs requires extensive knowledge, research, and experimentation, a process that is usually unpredictable, time-consuming and costly.

[0006] The aim of the present invention is to provide combinations of drugs with synergistic effects on cancer treatment, and methods of use thereof.

[0009] SUMMARY

[0010]

[0008] In some aspects, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject:

[0011] (a) a compound represented by the structure of Formula (II): wherein

[0012] U and Z are each independently N or CH;

[0013] X is O, NH, S, or a bond;

[0014] Y is CH2, C=O, or C=S;

[0015] R1is aryl, heteroaryl, or C(=O)-ORa, wherein aryl and heteroaryl are each optionally substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR4, NR5aR5b, or a combination thereof;

[0016] R2and R3are each independently at each occurrence selected from the group consisting of halogen, NO2, CN, C1-C4 alkyl, OR4, and NR5aR5b;

[0017] R4, Ra, R5a, and R5bare each independently hydrogen or C1-C4 alkyl; n is 0 or 1; m is 0, 1, or 2; p and q are each independently selected from 0, 1, 2, 3, and 4; or a pharmaceutically acceptable salt thereof; and

[0018] (b) a chemotherapeutic and / or a targeted therapy agent, or a pharmaceutically acceptable salt thereof.

[0019]

[0009] In some aspects, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a salt thereof; and (b) cisplatin or a salt thereof.

[0020]

[0010] In some aspects, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a salt thereof; and (b) sorafenib or a salt thereof.

[0021] [Oi l] In some aspects, disclosed herein is a method of increasing cisplatin anti-tumor effect in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.

[0022]

[0012] In some aspects, disclosed herein is a method of increasing sorafenib anti-tumor effect in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23):

[0023] or a pharmaceutically acceptable salt thereof.

[0024]

[0013] In some aspects, disclosed herein is a method for reducing tumor cell viability, comprising providing to a subject a composition comprising a compound represented by Formula (23): and cisplatin, or pharmaceutically acceptable salts thereof.

[0025]

[0014] In some aspects, disclosed herein is a method for reducing tumor cell viability, comprising providing to a subject a composition comprising a compound represented by Formula (23): and sorafenib, or pharmaceutically acceptable salts thereof.

[0026]

[0015] In some aspects, disclosed herein is a pharmaceutical composition comprising a compound represented by Formula (23): and cisplatin, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0027]

[0016] In some aspects, disclosed herein is a pharmaceutical composition comprising a compound represented by Formula (23): and sorafenib, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable earner.

[0028] BRIEF DESCRIPTION OF THE DRAWINGS

[0029]

[0017] The subject matter regarded as methods of treating cancer by the combinations disclosed herein, are particularly pointed out and distinctly claimed in the concluding portion of the specification. The compositions and methods of uses thereof, however, may best be understood by reference to the description provided herein when read with the accompanying drawings in which:

[0030]

[0018] Figure 1. Dose-dependent effect of Compound (23) on cancer proliferation and viability (dark section of each column) in vitro. HepG2 cells (10,000 / well) were treated with increasing concentrations of Compound (23). After 72 h, cells were tested for proliferation using EdU staining and live cells were determined by DRAQ7 staining.

[0031]

[0019] Figure 2A. Dose-dependent effect of sorafenib on liver cancer cell proliferation (squares) and viability (circles). HepG2 cells (10,000 / well) were treated with increasing concentrations of sorafenib and were stained with EdU staining and DRAQ7 after 72 h.

[0020] Figure 2B. Dose-dependent effect of cisplatin on liver cancer cell proliferation (squares) and viability (circles). HepG2 cells (10,000 / well) were treated with increasing concentrations of cisplatin and were stained with EdU staining and DRAQ7 after 72 h.

[0032]

[0021] Figure 3. The effect of treatment with Compound (23) and / or cisplatin on tumor size in an in vivo mouse model of colon cancer (CT-26 colon cancer cells in BALB / c mice). Data is presented for mice (n=10 / group) treated with cisplatin (1 mg / kg, twice a week), Compound (23) (400mg / kg PO, QD), or with a combination of cisplatin and Compound (23). Tumor size was measured according to the formula: tumor size = A x B2, where A is the length (the long dimension of the tumor), B is the width, and tumor size is measured in mm3.

[0033]

[0022] Figures 4A-4E. The effect of treatment with Compound (23) and / or cisplatin on tumor growth inhibition on day 38. Mice were treated with cisplatin (1 or 0.5 mg / kg, twice a week), Compound (23) (400mg / kg PO, QD), or with a combination of cisplatin and Compound (23). Tumor size was measured according to the formula: tumor size = A x B2, where A is the length (the long dimension of the tumor), B is the width, and tumor size is measured in mm3. Significant TGI was shown in animals treated with cisplatin 0.5 mg / kg + Compound (23), cisplatin 1 mg / kg alone, and cisplatin 1 mg / kg + Compound (23), with the combination treatment having the strongest effect.

[0034] * p-value < 0.05, **p-value< 0.005.

[0035]

[0023] Figure 5. The probability of survival for animals treated with Compound (23) and / or cisplatin over the first 50 days of the experiment. A significant increase in survival probability was shown in animals treated with cisplatin 1 mg / kg + Compound (23) compared to vehicle-administered animals, p-value < 0.0041 .

[0036] DETAILED DESCRIPTION

[0037]

[0024] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the methods for treating cancer disclosed herein, which comprise providing compounds represented by the structure of Formula (II) and chemotherapeutic and / or targeted therapy agents, as well as by providing compounds represented by Formula (23) and cisplatin or sorafenib. However, it will be understood by those skilled in the art that these methods and compositions can be useful also without the specific embodiments detailed below. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the descriptions herein. Methods of treating a hyperproliferative disorder

[0038]

[0025] In some embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof by providing a compound of Formula (II) and a chemotherapeutic and / or a targeted therapy agent to the subject. In some embodiments, treating a cancer comprises blocking cancer cell proliferation, inducing apoptosis in cancer cells, decreasing cancer cell viability, creating a pro-inflammatory environment within a tumor, or a combination thereof.

[0039]

[0026] In some embodiments, disclosed herein is a method for inhibiting a cancer or other hyperproliferative disorder in a subject in need thereof by providing a compound of Formula (II) and a chemotherapeutic and / or a targeted therapy agent to the subject.

[0040]

[0027] In some embodiments, disclosed herein is a method for suppressing a cancer or other hyperproliferative disorder in a subject in need thereof by providing a compound of Formula (II) and a chemotherapeutic and / or a targeted therapy agent to the subject.

[0041]

[0028] In some embodiments, disclosed herein is a method for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent.

[0042]

[0029] In some embodiments, disclosed herein is a method for increasing the anti-tumor effect of a chemotherapeutic agent in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II). In other embodiments, disclosed herein is a method for synergistically increasing the anti-tumor effect of a chemotherapeutic agent in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II).

[0043]

[0030] In some embodiments, disclosed herein is a method for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a targeted therapy agent.

[0044]

[0031] In some embodiments, disclosed herein is a method for increasing the anti-tumor effect of a targeted therapy in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II). In other embodiments, disclosed herein is a method for synergistically increasing the anti-tumor effect of a targeted therapy in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II).

[0032] In some embodiments, disclosed herein is a method for decreasing the viability of hyperproliferative cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent. In other embodiments, disclosed herein is a method for synergistically decreasing the viability of hyperproliferative cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent. In other embodiments, disclosed herein is a method for synergistically increasing the inhibition of cancer cell viability in a subject.

[0045]

[0033] In some embodiments, disclosed herein is a method for decreasing the viability of hyperproliferative cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a targeted therapy. In other embodiments, disclosed herein is a method for synergistically decreasing the viability of hyperproliferative cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a targeted therapy. In other embodiments, disclosed herein is a method for synergistically increasing the inhibition of cancer cell viability in a subject.

[0046]

[0034] In other embodiments, disclosed herein is a method for decreasing the viability of cancer cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic and / or a targeted therapy agent. In other embodiments, disclosed herein is a method for synergistically decreasing the viability of cancer cells in a subject having a hyperproliferative disorder, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic and / or a targeted therapy agent. In other embodiments, disclosed herein is a method for synergistically increasing the inhibition of cancer cell viability in a subject.

[0047]

[0035] In some embodiments, disclosed herein is a method for blocking cancer cell proliferation by providing a compound of Formula (II) and a chemotherapeutic and / or a targeted therapy agent to a subject in need thereof. In other embodiments, disclosed herein is a method for inducing apoptosis in cancer cells by providing a compound of Formula (II) and a chemotherapeutic and / or a targeted therapy agent to a subject in need thereof. In other embodiments, disclosed herein is a method for changing the inflammatory environment within a tumor by providing a compound of Formula (II) and a chemotherapeutic and / or a targeted therapy agent to a subject in need thereof. In one embodiment, the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment. In other embodiments, disclosed herein is a method for decreasing cancer cell viability by providing a compound of Formula (II) and a chemotherapeutic and / or a targeted therapy agent to a subject in need thereof.

[0048]

[0036] In some embodiments, disclosed herein is a method for blocking cancer cell proliferation by providing Compound (23) and a chemotherapeutic agent to a subject in need thereof. In some embodiments, disclosed herein is a method for inducing apoptosis in cancer cells by providing Compound (23) and a chemotherapeutic agent to a subject in need thereof. In other embodiments, disclosed herein is a method for changing the inflammatory environment within a tumor by providing Compound (23) and a chemotherapeutic agent to a subject in need thereof. In one embodiment, the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment. In other embodiments, disclosed herein is a method for decreasing cancer cell viability by providing Compound (23) and a chemotherapeutic agent to a subject in need thereof.

[0049]

[0037] In some embodiments, disclosed herein is a method for blocking cancer cell proliferation by providing Compound (23) and a targeted therapy or targeting agent to a subject in need thereof. In some embodiments, disclosed herein is a method for inducing apoptosis in cancer cells by providing Compound (23) and a targeted therapy or targeting agent to a subject in need thereof. In other embodiments, disclosed herein is a method for changing the inflammatory environment within a tumor by providing Compound (23) and a targeted therapy or targeting agent to a subject in need thereof. In one embodiment, the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment. In other embodiments, disclosed herein is a method for decreasing cancer cell viability by providing Compound (23) and a targeted therapy or targeting agent to a subject in need thereof.

[0038] In some embodiments, disclosed herein is a method for blocking cancer cell proliferation by providing Compound (23) and cisplatin to a subject in need thereof. In some embodiments, disclosed herein is a method for inducing apoptosis in cancer cells by providing Compound (23) and cisplatin to a subject in need thereof. In other embodiments, disclosed herein is a method for changing the inflammatory environment within a tumor by providing Compound (23) and cisplatin to a subject in need thereof. In one embodiment, the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment. In other embodiments, disclosed herein is a method for decreasing cancer cell viability by providing Compound (23) and cisplatin to a subject in need thereof.

[0039] In some embodiments, disclosed herein is a method for blocking cancer cell proliferation by providing Compound (23) and sorafenib to a subject in need thereof. In some embodiments, disclosed herein is a method for inducing apoptosis in cancer cells by providing Compound (23) and sorafenib to a subject in need thereof. In other embodiments, disclosed herein is a method for changing the inflammatory environment within a tumor by providing Compound (23) and sorafenib to a subject in need thereof. In one embodiment, the change in the inflammatory environment within a tumor is the creation of a pro-inflammatory environment. In other embodiments, disclosed herein is a method for decreasing cancer cell viability by providing Compound (23) and sorafenib to a subject in need thereof.

[0050]

[0040] In some embodiments, “providing” a compound to a subject comprises administering the compound to the subject. In some embodiments, administering the compound is via parenteral administration, intravenous administration, oral administration, rectal administration, intranasal administration, topical administration, or administration by inhalation.

[0051]

[0041] In some embodiments, “treating” or “treatment” refers to ameliorating or causing regression of the disease or the symptoms of the disease; inhibiting the disease or arresting its development; or preventing the symptoms or disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease. As understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of this disclosure, beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition, stabilizing (i.e., not worsening) state of a condition, delay or slowing of condition, progression, amelioration or palliation of the condition, states and remission (whether partial or total), whether detectable or undetectable.

[0052]

[0042] The terms “cancer,” “neoplasm,” and “tumor,” used interchangeably and in either the singular or plural form, refer to cells that have undergone a malignant transformation that makes them pathological to the host organism. Non-limiting examples of cancers that may be treated according to the methods of the present disclosure include a solid tumor or a non-solid tumor.

[0053]

[0043] An artisan would appreciate that a “subject” refers to an organism that can benefit from receiving a treatment comprising a chemotherapeutic and / or a targeted therapy agent, cisplatin, or sorafenib. In some embodiments, the term subject refers to a cancer patient. In some embodiments, the term subject refers to a human with predisposition to develop a malignancy. In some embodiments, the term subject refers to a human being. In some embodiments, the term subject refers to an animal.

[0054]

[0044] In other embodiments, the term “subject” refers to any organism who is suffering or at risk of a disease or disorder or condition. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a subject is a human. In some embodiments, a subject is suffering from or susceptible to one or more diseases or disorders or conditions. In some embodiments, a subject displays one or more symptoms of a disease or disorder or condition. In some embodiments, a subject has been diagnosed with one or more diseases or disorders or conditions, which, in some embodiments, is amenable to the technologies described herein.

[0055]

[0045] Tumors for which the present treatment methods are useful include any malignant cell type, such as those found in a solid tumor or a hematological or non-solid tumor. Exemplary solid tumors can include, but are not limited to, a tumor of an organ selected from the group consisting of pancreas, colon, cecum, stomach, brain, head, neck, ovary, kidney, larynx, sarcoma, lung, bladder, melanoma, prostate, and breast. Exemplary hematological tumors include tumors of the bone marrow, T or B cell malignancies, leukemias, lymphomas, blastomas, myelomas, and the like. Further examples of cancers that may be treated using the methods provided herein include, but are not limited to, lung cancer (including small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, gastric or stomach cancer (including gastrointestinal cancer and gastrointestinal stromal cancer), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, various types of head and neck cancer, skin cancer, bone cancer, and melanoma. In some embodiments, the solid tumor comprises a colon cancer, which in some embodiments, comprise adenocarcinoma. In other embodiments, the colon cancer comprises primary colorectal lymphomas, gastrointestinal stromal tumors, leiomyosarcomas, carcinoid tumors, melanomas, or a combination thereof. In other embodiments, the solid tumor comprises a liver cancer, which in some embodiments, comprise hepatocellular carcinoma (HCC; hepatoma), cholangiocarcinoma (bile duct cancer), and angiosarcoma.

[0056]

[0046] In some embodiments, the cancer comprises a lymphoproliferative disorder. In other embodiments, the cancer comprises a cancer of the central nervous system or cancer of the peripheral nervous system.

[0047] In some embodiments, a non-solid tumor as described herein comprises a hematologic cancer, acute myelogenous leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin’s lymphoma, nonHodgkin’s lymphoma, cutaneous T-cell lymphoma, or metastases thereof.

[0057]

[0048] The cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; paget's disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w / squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; Sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; lentigo malignant melanoma; acral lentiginous melanomas; nodular melanomas; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi's sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacorti cal osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing's sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; gangboneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; hodgkin's disease; hodgkin's; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fimgoides; other specified non-hodgkin's lymphomas; B-cell lymphoma; low grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; Waldenstrom's macroglobulinemia; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; hairy cell leukemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); myelodysplastic syndrome (MDS); chronic myeloblasts leukemia; diffuse large B-cell lymphoma (DLBCL); peripheral T-cell lymphoma (PTCL); or anaplastic large cell lymphoma (ALCL). In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is AML. In other embodiments, the cancer comprises an esophageal carcinoma, a thyroid carcinoma, ganglioblastoma, osteogenic sarcoma, endotheliosarcoma, Ewing’s tumor, leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, adenocarcinoma, renal cell carcinoma, hypernephroma, hypemephroid adenocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, testicular tumor, lung carcinoma, bladder carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, neuroblastoma, colon carcinoma, rectal carcinoma, hematopoietic or hematologic malignancies, or metastases thereof..

[0058]

[0049] In some embodiments, at least one further agent effective at treating cancer is administered to said subject. In some embodiments, radiation therapy is administered to said subject.

[0059] Compounds of Formula (II)

[0060]

[0050] In some embodiments, disclosed herein are methods for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof, said methods comprising providing to said subject

[0061] (a) a compound represented by the structure of Formula (II): wherein

[0062] U and Z are each independently N or CH;

[0063] X is O, NH, S, or a bond;

[0064] Y is CH2, C=O, or C=S;

[0065] R1is aryl, heteroaryl, or C(=O)-ORa, wherein aryl and heteroaryl are each optionally substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR4, NR5aR5b, or a combination thereof;

[0066] R2and R3are each independently at each occurrence selected from the group consisting of: halogen, NO2, CN, C1-C4 alkyl, OR4, and NR5aR5b;

[0067] R4, Ra, R5a, and R5bare each independently hydrogen or C1-C4 alkyl; n is 0 or 1; m is 0, 1, or 2; p and q are each independently selected from 0, 1, 2, 3, and 4; or a pharmaceutically acceptable salt thereof; and (b) a chemotherapeutic and / or a targeted therapy agent.

[0068]

[0051] In some embodiments, the following compound is excluded: a compound of Formula (II) wherein X is NH, Z is CH, Y is C=O, n is 0, m is 0, R1is a phenyl substituted by one or more alkoxy, and p and q are each 0.

[0069]

[0052] In some embodiments, in the compound of Formula (II), m and n are each 0. In some embodiments, in the compound of Formula (II), R1is aryl or heteroaryl. In some embodiments, R1is phenyl, quinolinyl, or isoquinolinyl. In other embodiments, R1is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR4, or a combination thereof. In certain embodiments, R1is C(=O)-ORa, wherein Rais C1-C4 alkyl.

[0070]

[0053] In some embodiments, R2is H. In some embodiments, R3is H. In other embodiments, R2is H and R3is H. In some embodiments, in the compound of Formula (II), p is 0. In some embodiments, q is 0. In other embodiments, p is 0 and q is 0. In some embodiments, in the compound of Formula (II), U is N.

[0071]

[0054] In some embodiments, the compound provided in the methods disclosed herein, and together with a chemotherapeutic and / or a targeted therapy agent is represented by the structure of Formula (III): wherein X, U, R1, R2, R3, m, n, p, and q are defined as described herein; and a chemotherapeutic and / or a targeted therapy agent.

[0072]

[0055] In some embodiments, in the compound of Formula (III), X is O, NH, or a bond. In some embodiments, X is O. In other embodiments, X is a bond. In certain embodiments, X is NH.

[0073]

[0056] In some embodiments, in the compound of Formula (III), m and n are each 0.

[0074]

[0057] In some embodiments, in the compound of Formula (III), R1is aryl or heteroaryl. In some embodiments, R1is phenyl, quinolinyl, or isoquinolinyl. In other embodiments, R1is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR4, or a combination thereof. In certain embodiments, R1is C(=O)-ORa, wherein Rais C1-C4 alkyl.

[0075]

[0058] In some embodiments, R2is H. In some embodiments, R3is H. In other embodiments, R2is H and R3is H.

[0059] In some embodiments, in the compound of Formula (III), p is 0. In some embodiments, q is 0. In other embodiments, p is 0 and q is 0.

[0076]

[0060] In some embodiments, in the compound of Formula (III), U is N.

[0077]

[0061] In some embodiments, the compound provided in the methods disclosed herein is represented by the structure of Formula (IV). wherein X, U, R1, R2, R3, m, n, p, and q are defined as described herein.

[0078]

[0062] In some embodiments, in the compound of Formula (IV), X is O. In other embodiments, X is S. In certain embodiments, X is NH.

[0079]

[0063] In some embodiments, in the compound of Formula (IV), R1is aryl or heteroaryl. In some embodiments, R1is phenyl, quinolinyl, or isoquinolinyl. In other embodiments, R1is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR4, or a combination thereof. In certain embodiments, R1is C(=O)-ORa, wherein Rais C1-C4 alkyl.

[0080]

[0064] In some embodiments, R2is H. In some embodiments, R3is H. In other embodiments, R2is H and R3is H.

[0081]

[0065] In some embodiments, in the compound of Formula (IV), p is 0. In some embodiments, q is 0. In other embodiments, p is 0 and q is 0.

[0082]

[0066] In some embodiments, in the compound of Formula (IV), U is N.

[0083]

[0067] In some embodiments, the compound provided together with a chemotherapeutic and / or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is:

[0068] In other embodiments, the compound is:

[0084]

[0069] In other embodiments, the compound is:

[0070] In other embodiments, the compound is:

[0085]

[0071] In other embodiments, the compound is:

[0072] In other embodiments, the compound is:

[0086]

[0087]

[0073] In other embodiments, the compound is:

[0088]

[0074] In other embodiments, the compound is:

[0089]

[0075] In other embodiments, the compound is:

[0090]

[0076] In other embodiments, the compound is:

[0091]

[0077] In some embodiments, the compound is a combination of the compounds above. In some embodiments, the compounds described may be salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, or mixtures of the compounds.

[0092]

[0078] In some embodiments, the compound provided together with a chemotherapeutic and / or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is represent by Formula (V): wherein X, U, R1, R2, R3, m, n, p, and q are defined as described herein.

[0093]

[0079] In some embodiments, in the compound of Formula (V), Z is N. In other embodiments,

[0094] Z is CH.

[0095]

[0080] In some embodiments, in the compound of Formula (V), R1is aryl or heteroaryl. In some embodiments, R1is phenyl, quinolinyl, or isoquinolinyl. In other embodiments, R1is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR4, or a combination thereof. In certain embodiments, R1is C(=O)-ORa, wherein Rais C1-C4 alkyl. In some embodiments, R2is H. In some embodiments, R3is H. In other embodiments, R2is H and R3is H.

[0096]

[0081] In some embodiments, in the compound of Formula (V), p is 0. In some embodiments, q is 0. In other embodiments, p is 0 and q is 0.

[0097]

[0082] In some embodiments, in the compound of Formula (V), U is N.

[0098]

[0083] In some embodiments, the compound provided together with a chemotherapeutic and / or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is:

[0099]

[0084] In other embodiments, the compound is:

[0100]

[0085] In other embodiments, the compound is:

[0101]

[0086] In other embodiments, the compound is:

[0087] In some embodiments, the compound is a combination of the compounds above. In some embodiments, the compounds described may be salts, hydrates, solvates, polymorphs, optical isomers, geometrical isomers, enantiomers, diastereomers, or mixtures of the compounds.

[0102]

[0088] In some embodiments, the compound provided together with a chemotherapeutic and / or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is represented by the structure of Formula (VI):

[0103] wherein U, R1, R2, R3, p, and q are defined as described herein.

[0104]

[0089] In some embodiments, in the compound of Formula (VI), R1is aryl or heteroaryl. In some embodiments, R1is phenyl, quinolinyl, or isoquinolinyl. In other embodiments, R1is phenyl, optionally substituted with one or more halogen, CN, C1-C4 alkyl, OR4, or a combination thereof. In certain embodiments, R1is C(=O)-ORa, wherein Rais C1-C4 alkyl. In some embodiments, R2is H. In some embodiments, R3is H. In other embodiments, R2is H and R3is H.

[0105]

[0090] In some embodiments, in the compound of Formula (VI), p is 0. In some embodiments, q is 0. In other embodiments, p is 0 and q is 0.

[0106]

[0091] In some embodiments, in the compound of Formula (VI), U is N.

[0107]

[0092] In some embodiments, the compound provided together with a chemotherapeutic and / or a targeted therapy agent as disclosed in the methods, compositions, and combinations disclosed herein is:

[0108]

[0093] In another embodiment, R1is selected from the group consisting of phenyl, quinolinyl and isoquinolinyl, each of which may independently be unsubstituted or substituted with one or more halogen, ORaor NRaRbwherein Raand Rbare each independently selected from the group consisting of H or a C1-C4 alkyl.

[0109]

[0094] In another embodiment, R1is C(=O)-ORawherein Rais a C1-C4 alkyl. In other embodiments, R1is selected from the group consisting of: a) phenyl; b) fluorophenyl; c) difluorophenyl; d) pentafluorophenyl ; e) methoxyphenyl ; f) g) C(=O)-OCH2CH3.

[0110]

[0095] Each possibility represents a separate embodiment of the present invention.

[0111]

[0096] In some embodiments, in the compound of Formula (II) or in the compound of Formula (IV), X is S. In one embodiment, when X is S, Z is CH. In an alternative embodiment, the following compound is excluded: a compound of Formula (II) wherein X is S, Z is N, Y is C=O, n is 0, m is 0, R1 is an unsubstituted or substituted phenyl and p and q are each 0. In another embodiment, the following compound is excluded: a compound of formula (II) wherein X is S, Z is N, Y is C=O, n is 0, m is 0, R1is pyridinyl and p and q are each 0.

[0112]

[0097] In some embodiments wherein X is S, R1is aryl, optionally substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR4, and NR5aR5b, or a combination thereof. In some embodiments wherein X is S, R1is aryl substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR4, and NR5aR5b, or a combination thereof. In some embodiments wherein X is S, R1is aryl substituted with one or more alkyl, arylalkyl, halogen, NO2, and NR5aR5b, or a combination thereof. In some embodiments wherein X is S, R1is phenyl substituted with one or more alkyl, arylalkyl, halogen, NO2, and NR5aR5b, or a combination thereof. In some embodiments wherein X is S, R1is aryl, optionally substituted with one or more halogen and C1-C4 alkyl, or a combination thereof. In some embodiments wherein X is S, R1is phenyl, optionally substituted with one or more halogen and C1-C4 alkyl, or a combination thereof.

[0113]

[0098] In some embodiments wherein X is S, R1is heteroaryl, optionally substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR4, and NR5aR5b, or a combination thereof. In some embodiments wherein X is S, R1is not pyridinyl. In some embodiments wherein X is S, R1is heteroaryl substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR4, and NR5aR5b, or a combination thereof. In some embodiments wherein X is S, R1is heteroaryl substituted with one or more alkyl, arylalkyl, halogen, NO2, and NR5aR5b, or a combination thereof. In some embodiments wherein X is S, R1is quinolinyl, or isoquinolinyl. In some embodiments wherein X is S, R1is quinolinyl or isoquinolinyl, optionally substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR4, and NR5aR5b, or a combination thereof. In some embodiments wherein X is S, R1is quinolinyl or isoquinolinyl, optionally substituted with one or more halogen and C1-C4 alkyl, or a combination thereof. In certain embodiments wherein X is S, R1is C(=O)-ORa, wherein Rais C1-C4 alkyl.

[0114]

[0099] In one embodiment, the compound represented by the structure of Formula (II) as described herein is as described but having the proviso that:

[0115] (1) when Z is CH, X is NH, S, or a bond;

[0116] (2) when X is S, Z is CH; and

[0117] (3) the following compound: a compound of Formula (II) wherein X is NH, Z is CH, Y is C=O, n is 0, m is 0, R1is a phenyl substituted by one or more alkoxy, and p and q are each 0, is excluded.

[0118]

[0100] In another embodiment, the compound represented by the structure of Formula (II) as described herein is as described but having the proviso that:

[0119] (1) when Z is CH, X is NH, S, or a bond and

[0120] (2) the following compounds are excluded:

[0121] (i) a compound of Formula (II) wherein X is NH, Z is CH, Y is C=O, n is 0, m is 0, R1 is a phenyl substituted by one or more alkoxy, and p and q are each 0; and

[0122] (ii) a compound of Formula (II) wherein X is S, Z is N, Y is C=O, n is 0, m is 0, R1 is an unsubstituted or substituted phenyl and p and q are each 0.

[0123]

[0101] In another embodiment, the compound represented by the structure of Formula (II) as described herein is as described but having the proviso that:

[0124] (1) when Z is CH, X is NH, S, or a bond;

[0125] (2) the following compounds are excluded:

[0126] (i) a compound of formula (II) wherein X is NH, Z is CH, Y is C=O, n is 0, m is 0, R1is a phenyl substituted by one or more alkoxy, and p and q are each 0; and

[0127] (ii) a compound of formula (II) wherein X is S, Z is N, Y is C=O, n is 0, m is 0, R1is pyridinyl and p and q are each 0.

[0128]

[0102] In one embodiment, the compound is represented by the structure of Formula (II), wherein n is 0. According to this aspect and in one embodiment, the compound is represented by the structure of Formula (II-a):

[0129]

[0103] In another embodiment, the compound is represented by Formula (II) wherein X is O, Z is N, Y is C=O, n is 0, m is 0, R1is phenyl or methoxyphenyl and p and q are each 0.

[0130]

[0104] In yet another embodiment, the compound is represented by Formula (II) wherein X is S, Z is CH, Y is C=O, n is 0, m is 0, R1is phenyl and p and q are each 0.

[0131]

[0105] In one embodiment, the compound is represented by Formula (II) wherein X is O, Z is N, Y is C=O, n is 0, m is 0, R1is methoxyphenyl and p and q are each 0. In another embodiment, the compound is represented by Formula (II), wherein X is O, Z is N, Y is C=O, n is 0, m is 0, R1is difluorophenyl or pentafluorophenyl and p and q are each 0.

[0132]

[0106] In another embodiment the compound is represented by Formula (II), wherein p and q are each 0 (i.e., R2and R3do not exist).

[0133]

[0107] As used herein, in some embodiments, an “alkyl” group refers to any saturated aliphatic hydrocarbon, including straight-chain and branched-chain alkyl groups. In one embodiment, the alkyl group has 1-4 carbons designated here as C1-C4 -alkyl. In some embodiments, the alkyl group has 1-7 carbons designated here as Ci-C?-alkyl. The alkyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.

[0134]

[0108] The term “aryl” used herein alone or as part of another group denotes an aromatic ring system containing from 6-14 ring carbon atoms. The aryl ring can be a monocyclic, bicyclic, tricyclic and the like. Non-limiting examples of aryl groups are phenyl, naphthyl including 1- naphthyl and 2-naphthyl, and the like. The aryl group can be unsubstituted or substituted through available carbon atoms with one or more groups defined hereinabove for alkyl.

[0135]

[0109] The term “heteroaryl” used herein alone or as part of another group denotes a heteroaromatic system containing at least one heteroatom ring atom selected from nitrogen, sulfur and oxygen. The heteroaryl contains 5 or more ring atoms. In some embodiments, the heteroaryl group contains 5-10 ring atoms. The heteroaryl group can be monocyclic, bicyclic, tricyclic and the like. Also included in this expression are the benzoheterocyclic rings. If nitrogen is a ring atom, the present invention also contemplates the N-oxides of the nitrogen containing heteroaryls. Nonlimiting examples of heteroaryls include thienyl, benzothienyl, 1- naphthothienyl, thianthrenyl, furyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, purinyl, quinolyl (e.g. 1- quinolinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7-quinolinyl and 8-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 2-isoquinolinyl, 3-isoquinolinyl, 4- isoquinolinyl, 5-isoquinolinyl, 6-isoquinolinyl, 7-isoquinolinyl and 8-isoquinolinyl); naphthyridinyl (e.g., 1-naphthyridinyl, 2-naphthyridinyl), quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbolinyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl and the like. The heteroaryl group can optionally be substituted through available atoms with one or more groups defined hereinabove for alkyl. The heteroaryl group can be unsubstituted or substituted through available atoms with one or more groups defined hereinabove for alkyl.

[0136]

[0110] The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.

[0137]

[0111] The term “hydroxy” refers to an OH group. The terms "alkoxy" refers to the group ORawherein Rais a C1-C4 alkyl as defined above. Nonlimiting examples of an alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups.

[0138]

[0112] All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the atoms. Consequently, the compounds can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The present invention contemplates the use of any racemates (i.e. mixtures containing equal amounts of each enantiomers), enantiomerically enriched mixtures (i.e., mixtures enriched for one enantiomer), pure enantiomers or diastereomers, or any mixtures thereof. The chiral centers can be designated as R or S or R,S or d,D, 1,L or d,l, D,L. The present invention intends to encompass all structural and geometrical isomers including cis, trans, E and Z isomers.

[0139]

[0113] One or more of the compounds of the invention, may be present as a salt. The term "salt" encompasses both basic and acid addition salts, including but not limited to, carboxylate salts or salts with amine nitrogens, and include salts formed with the organic and inorganic anions and cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D- camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicylic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids. Each possibility represents a separate embodiment of the invention.

[0140]

[0114] The term "organic or inorganic cation" refers to counter-ions for the anion of a salt. The counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium); ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyclohexylamine; and the organic cations, such as dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2- hydroxyethyl)ammonium, phenylethylbenzylammonium, dibenzylethylene diammonium, and like cations. See, for example, "Pharmaceutical Salts," Berge et al., J. Pharm. Sci., 66: 1-19 (1977), which is incorporated herein by reference.

[0141]

[0115] The present invention also includes solvates of the compounds of the present invention and salts thereof. “Solvate” means a physical association of a compound of the invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. “Hydrate” is a solvate wherein the solvent molecule is water.

[0142]

[0116] The present invention also includes polymorphs of the compounds of the present invention and salts thereof. The term “polymorph” refers to a particular crystalline state of a substance, which can be characterized by particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.

[0143]

[0117] In some embodiments, the present disclosure provides compositions comprising the compounds of Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Compound (23), Compounds (l)-(2), (4)-(5), (11)-(16), or Compound (3).

[0144] Chemotherapeutic agents

[0145]

[0118] In some embodiments, disclosed herein is a method for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a chemotherapeutic agent.

[0146]

[0119] In some embodiments, disclosed herein is a method for increasing the anti-tumor effect of a chemotherapeutic agent in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II). In other embodiments, disclosed herein is a method for synergistically increasing the anti-tumor effect of a chemotherapeutic agent in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II).

[0147]

[0120] A skilled artisan will appreciate that a chemotherapeutic agent, which can also be termed “antineoplastic agent” or “cytotoxic drug”, having all the same limitations and features, are a diverse group of pharmacological compounds employed to treat cancer. Any chemotherapeutic agent can be used in combination with a compound represented by the structure of Formula (II).

[0148]

[0121] In some embodiments, a chemotherapeutic agent comprises an alkylating agent. In some embodiments, a chemotherapeutic agent comprises an antimetabolite. In some embodiments, a chemotherapeutic agent comprises an antitumor antibiotic. In some embodiments, a chemotherapeutic agent comprises a hormonal agent. In some embodiments, the chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an antitumor antibiotic, a hormonal agent, or a combination thereof. In some embodiments, the chemotherapeutic agent is selected from the group consisting of an alkylating agent, an antimetabolite, an antitumor antibiotic, a hormonal agent, and a combination thereof.

[0149]

[0122] In some embodiments, the alkylating agent comprises cisplatin, Cyclophosphamide, Carboplatin, Etoposide, Melphalan, or a combination thereof. In some embodiments, the alkylating agent is selected from the group consisting of cisplatin, Cyclophosphamide, Carboplatin, Etoposide, and Melphalan. In some embodiments, the antimetabolite is selected from the group consisting of Methotrexate, 5 -fluorouracil (5-FU), Mercaptopurine, Cytosine arabinoside (Ara-C), and Cladribine. In some embodiments, the antimetabolite comprises Methotrexate, 5 -fluorouracil (5-FU), Mercaptopurine, Cytosine arabinoside (Ara-C), Cladribine, or a combination thereof. In some embodiments, the antitumor antibiotic comprises Actinomycin D, Dactinomycin, Doxorubicin, Bleomycin, Mitomycin C, or a combination thereof. In some embodiments, the antitumor antibiotic is selected from the group consisting of Actinomycin D, Dactinomycin, Doxorubicin, Bleomycin, and Mitomycin C. In some embodiments, the hormonal agent comprises Tamoxifen, Anastrozole, Letrozole, Exemestane, Fulvestrant, or a combination thereof. In some embodiments, the hormonal agent is selected from the group consisting of Tamoxifen, Anastrozole, Letrozole, Exemestane, and Fulvestrant.

[0150]

[0123] In some embodiments, the methods comprise administering a compound of Formula (II) and cisplatin. In some embodiments, the methods comprise administering a compound of Formula (II) and Cyclophosphamide. In some embodiments, the methods comprise administering a compound of Formula (II) and Carboplatin. In some embodiments, the methods comprise administering a compound of Formula (II) and Etoposide. In some embodiments, the methods comprise administering a compound of Formula (II) and Melphalan.

[0151]

[0124] In some embodiments, the methods comprise administering a compound of Formula (II) and Methotrexate. In some embodiments, the methods comprise administering a compound of Formula (II) and 5 -fluorouracil (5-FU). In some embodiments, the methods comprise administering a compound of Formula (II) and Mercaptopurine. In some embodiments, the methods comprise administering a compound of Formula (II) and Cytosine arabinoside (Ara- C). In some embodiments, the methods comprise administering a compound of Formula (II) and Cladribine.

[0152]

[0125] In some embodiments, the methods comprise administering a compound of Formula (II) and Actinomycin D. In some embodiments, the methods comprise administering a compound of Formula (II) and Dactinomycin. In some embodiments, the methods comprise administering a compound of Formula (II) and Doxorubicin. In some embodiments, the methods comprise administering a compound of Formula (II) and Bleomycin. In some embodiments, the methods comprise administering a compound of Formula (II) and Mitomycin C.

[0153]

[0126] In some embodiments, the methods comprise administering a compound of Formula (II) and Tamoxifen. In some embodiments, the methods comprise administering a compound of Formula (II) and Anastrozole. In some embodiments, the methods comprise administering a compound of Formula (II) and Letrozole. In some embodiments, the methods comprise administering a compound of Formula (II) and Exemestane. In some embodiments, the methods comprise administering a compound of Formula (II) and Fulvestrant.

[0154]

[0127] In some embodiments, the methods comprise administering a compound of Formula (II) and Trastuzumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Erlotinib. In some embodiments, the methods comprise administering a compound of Formula (II) and Gefitinib. In some embodiments, the methods comprise administering a compound of Formula (II) and Imatinib. In some embodiments, the methods comprise administering a compound of Formula (II) and Rituximab.

[0155]

[0128] In some embodiments, disclosed herein is a method for treating a cancer in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II) and an immune therapy or immunotherapy. In some embodiments, the immunotherapy comprises administration of Ipilimumab, Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab, or a combination thereof. In some embodiments, the immunotherapy is selected from the group consisting of Ipilimumab, Pembrolizumab, Nivolumab, Atezolizumab, and Durvalumab.

[0129] In some embodiments, the methods comprise administering a compound of Formula (II) and Ipilimumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Pembrolizumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Nivolumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Atezolizumab. In some embodiments, the methods comprise administering a compound of Formula (II) and Durvalumab.

[0156]

[0130] In some embodiments, the methods comprise administering a composition represented by Formula (II), a first chemotherapeutic agent, and a second chemotherapeutic agent. In some embodiments, the methods comprise administering a composition represented by Formula (II), and two or more chemotherapeutic agents.

[0157]

[0131] In some embodiments, the methods comprise administering a composition represented by Formula (II), a first chemotherapeutic agent, and a further cancer therapy not comprising chemotherapy. In some embodiments, the methods comprise administering a composition represented by Formula (II), a first chemotherapeutic agent, and radiotherapy.

[0158]

[0132] In some embodiments, the present disclosure provides compositions comprising a chemotherapeutic agent, which in one embodiment, is cisplatin. In other embodiments, the present disclosure provides compositions comprising a compound represented by the structure of Formula (II), which in one embodiment, is Compound (23), and a chemotherapeutic agent, which in one embodiment, is cisplatin.

[0159] Targeted therapy agents

[0160]

[0133] In some embodiments, disclosed herein is a method for treating, inhibiting, or suppressing a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II) and a targeted therapy agent.

[0161]

[0134] In some embodiments, disclosed herein is a method for increasing the anti-tumor effect of a targeted therapy in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II). In other embodiments, disclosed herein is a method for synergistically increasing the anti-tumor effect of a targeted therapy in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (II).

[0162]

[0135] In some embodiments, the targeted therapy agent comprises Sorafenib, Trastuzumab, Erlotinib, Gefitinib, Imatinib, Rituximab, or a combination thereof. In some embodiments, the targeted therapy agent is selected from the group consisting of Sorafenib, Trastuzumab, Erlotinib, Gefitinib, Imatinib, and Rituximab. In some embodiments, the targeted therapy agent comprises Sorafenib. In some embodiments, the targeted therapy agent comprises Trastuzumab. In some embodiments, the targeted therapy agent comprises Erlotinib. In some embodiments, the targeted therapy agent comprises Gefitinib. In some embodiments, the targeted therapy agent comprises Imatinib. In some embodiments, the targeted therapy agent comprises Rituximab. In some embodiments, the targeted therapy agent comprises a combination of the above targeted therapy agents.

[0163]

[0136] A skilled artisan will appreciate that a targeted therapy for cancer, which can also be termed “precision medicine”, “molecularly targeted therapy”, or “personalized cancer therapy”, having all the same limitations and features, refers to therapeutic approaches aimed at interfering with molecular processes that distinctly occur in cancer cells. Thus, contrary to traditional chemotherapeutic therapies, targeted therapies do not affect non-malignant cells.

[0164]

[0137] In some embodiments, a targeted therapy targets cells having a genetic mutation. In some embodiments, a targeted therapy comprises targeting cells overexpressing oncoproteins. In some embodiments, a targeted therapy targets cells with abnormal signaling pathways.

[0165]

[0138] A number of targeted therapy agents are available in the clinic, and many others are still on preclinical and clinical development. A skilled artisan would appreciate that any of these agents may be implemented in the method disclosed herein and may be administered with a compound of Formula (II).

[0166]

[0139] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a tyrosine kinase inhibitor (TKI). In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and imatinib. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and erlotinib. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and sunitinib.

[0167]

[0140] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a proteasome inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and bortezomib.

[0168]

[0141] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a monoclonal antibody. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and an epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and cetuximab. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and trastuzumab.

[0169]

[0142] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and programmed cell death protein- 1 (PD-1) inhibitors. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and pembrolizumab. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and nivolumab.

[0170]

[0143] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a hormone therapy. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a selective estrogen receptor modulator (SERM). In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and an aromatase inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and tamoxifen. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and letrozole.

[0171]

[0144] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and an androgen receptor blocker. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and enzalutamide.

[0172]

[0145] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and an apoptosis inducer. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a Bel -2 inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and venetoclax.

[0173]

[0146] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and an angiogenesis inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and a vascular endothelial growth factor (VEGF) inhibitor. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and bevacizumab.

[0174]

[0147] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and an immunotherapy. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and chimeric antigen receptor T (CAR-T) cells.

[0175]

[0148] In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and checkpoint inhibitors. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and PARP inhibitors. In some embodiments, the methods disclosed herein comprise administering a compound of Formula (II) and olaparib.

[0176]

[0149] In some embodiments, a compound represented by the structure of Formula (II) is provided to a subject in need thereof with two chemotherapeutic and / or targeted therapy agents disclosed herein. In some embodiments, a compound represented by the structure of Formula (II) is provided to a subj ect in need thereof with three chemotherapeutic and / or targeted therapy agents disclosed herein. In some embodiments, a compound represented by the structure of Formula (II) is provided to a subject in need thereof with more than three chemotherapeutic and / or targeted therapy agents disclosed herein.

[0177]

[0150] In some embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (III) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.

[0178]

[0151] In other embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (IV) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.

[0179]

[0152] In other embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject compound (1), compound (2), compound (4), compound (5), compound (11), compound (12), compound (13), compound (14), compound (15), compound (16) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.

[0180]

[0153] In other embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (V) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.

[0181]

[0154] In other embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject any one or more of compounds (20)-(23) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.

[0182]

[0155] In other embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by the structure of Formula (VI) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.

[0183]

[0156] In other embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject compounds (3) as described hereinabove and a chemotherapeutic agent, a targeted therapy agent, an immunotherapy, or a combination thereof as described hereinabove.

[0184]

[0157] In some embodiments, the present disclosure provides compositions comprising a targeted therapy agent, which, in one embodiment, is sorafenib. In other embodiments, the present disclosure provides compositions comprising a compound represented by the structure of Formula (II), which in one embodiment, is Compound (23), and a targeted therapy agent, which, in one embodiment, is sorafenib.

[0185] Compound (23) and sorafenib

[0186]

[0158] In certain embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a salt thereof; and (b) sorafenib or a salt thereof.

[0187]

[0159] The terms “Compound of Formula (23),” “compound represented by Formula (23),” “Compound 23,” and Compound (23) are used herein interchangeably having all the same features and limitation. Without being bound to any specific theory or mechanism of action, it has been found that Compound (23) selectively modulates the interaction between voltage-dependent anion channel 1 (VDAC) and hexokinase enzyme (HK)-2. In some embodiments, Compound (23) prevents the binding of HK2 and VDAC thus inducing apoptosis.

[0188]

[0160] Sorafenib, which, in some embodiments, is “Nexavar” or “Sorafenib tosylate” interchangeably, having all the same features and limitations, is a kinase inhibitor drug used for treatment of renal cell carcinoma (RCC), hepatocellular carcinomas (HCC) and thyroid cancer, among others.

[0189]

[0161] Without being bound to any specific theory, sorafenib acts by inhibiting protein kinases, including VEGFR, PDGFR and RAF kinases. By blocking RAF kinases, sorafenib disrupts downstream signaling, preventing the activation of MEK and ERK, and hindering cancer cell proliferation. Further, inhibition of VEGFR and PDGFR interferes with signaling pathways that promote angiogenesis and tumor growth.

[0190]

[0162] In some embodiments, disclosed herein is a method for increasing a sorafenib anti-tumor effect in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.

[0191]

[0163] In other embodiments, disclosed herein is a method for synergistically increasing a sorafenib anti-tumor effect in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.

[0164] In some embodiments, the effect of sorafenib is increased following administration of a compound represented by Formula (23). In some embodiments, the effect of sorafenib is increased by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, following administration of Compound (23).

[0192]

[0165] In some embodiments, the combination of Compound (23) and sorafenib induce a synergistic effect, i.e., the combination produces an effect that is greater than the sum of the separate effects of each component of the combination.

[0193]

[0166] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound represented by Formula (23): and sorafenib, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable earner.

[0194]

[0167] In some embodiments, a composition comprising Compound (23) and sorafenib is formulated for parenteral, oral, rectal, intranasal, topical, inhalation, intravenous, subcutaneous, intraperitoneal, intraarterial, transdermal, or intramuscular administration.

[0195]

[0168] In some embodiments, disclosed herein is a kit comprising a compound represented by Formula (23): and sorafenib, or pharmaceutically acceptable salts thereof, and instructions for use thereof.

[0196]

[0169] In other embodiments, the present disclosure provides compositions comprising Compound (23) and sorafenib. Compound (23) and cisplatin

[0197]

[0170] In certain embodiments, disclosed herein is a method for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a salt thereof; and (b) cisplatin or a salt thereof.

[0198]

[0171] The terms “Compound of Formula (23),” “compound represented by Formula (23),” “Compound 23,” and Compound (23) are used herein interchangeably having all the same features and limitation. Without being bound to any specific theory or mechanism of action, it has been found that Compound (23) selectively modulates the interaction between voltage-dependent anion channel 1 (VDAC) and hexokinase enzyme (HK)-2. In some embodiments, Compound (23) prevents the binding of HK2 and VDAC thus inducing apoptosis.

[0199]

[0172] cisplatin, which in some embodiments might be also termed cisplatinum, platamin, neoplatin, cismaplat, cis-diamminedichloroplatinum(II) (CDDP) interchangeably, having all the same features and limitations, is a chemotherapy medication used to treat a number of cancers. In some embodiments, cisplatin is administered intravenously in normal saline for treatment of solid and haematological malignancies. Without being bound to any scientific theory, in some embodiments, cisplatin may exert its effects by interfering with DNA replication, which kills the fastest proliferating cells, such as tumor cells.

[0200]

[0173] In some embodiments, disclosed herein is a method for increasing a cisplatin anti-tumor effect in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.

[0201]

[0174] In other embodiments, disclosed herein is a method for synergistically increasing a cisplatin anti-tumor effect in a subject in need thereof, said method comprising providing to said subject a compound represented by Formula (23): or a pharmaceutically acceptable salt thereof.

[0202]

[0175] In some embodiments, the effect of cisplatin is increased following administration of a compound represented by Formula (23). In some embodiments, the effect of cisplatin is increased by 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more than 100%, following administration of Compound (23).

[0203]

[0176] In some embodiments, the combination of Compound (23) and cisplatin induces a synergistic effect, i.e., it produces a combined effect greater than the sum of the effects of the separate components of the combination.

[0204]

[0177] In some embodiments, disclosed herein is a pharmaceutical composition comprising a compound represented by Formula (23):

[0205] and cisplatin, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable earner.

[0206]

[0178] In some embodiments, a composition comprising Compound (23) and cisplatin is formulated for parenteral, oral, rectal, intranasal, topical, inhalation, intravenous, subcutaneous, intraperitoneal, intraarterial, transdermal, or intramuscular administration.

[0207]

[0179] In some embodiments, disclosed herein is a kit comprising a compound represented by Formula (23): and cisplatin, or pharmaceutically acceptable salts thereof, and instructions for use thereof.

[0208]

[0180] In other embodiments, the present disclosure provides compositions comprising Compound (23) and cisplatin.

[0209] Pharmaceutical Compositions

[0210]

[0181] The compound represented by Formula (II), the compound represented by Formula (III), compound represented by Formula (IV), compound represented by Formula (V), compound represented by Formula (VI), the compound represented by Formula (23), other compounds described herein, the chemotherapeutic, the targeted therapy agent, cisplatin, and sorafenib which are referred to herein as “active compounds”, “active ingredients”, or the “compounds of the invention”, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the composition, for example the compound represented by Formula (23) and cisplatin, and a pharmaceutically acceptable carrier; or the compound represented by Formula (23) and sorafenib, and a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington’s Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, ringer’s solutions, dextrose solution, and 5% human serum albumin. Liposomes and nonaqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0211]

[0182] Pharmaceutical compositions and formulations as described herein can be prepared by mixing the active ingredients having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 22ndedition, 2012), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn- protein complexes); and / or non- ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include insterstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

[0212]

[0183] In some embodiments, the compounds of the invention are administered in the same pharmaceutical composition. In some embodiments, a compound represented by the structure of Formula (II) and a chemotherapeutic and / or a targeted therapy agent are administered in the same pharmaceutical composition. In some embodiments, a compound represented by the structure of Formula (23) and cisplatin are administered in the same pharmaceutical composition. In some embodiments, a compound represented by the structure of Formula (23) and sorafenib are administered in the same pharmaceutical composition.

[0213]

[0184] In some embodiments, the compounds of the invention are administered in separate pharmaceutical compositions. In some embodiments, a compound represented by the structure of Formula (II) and a chemotherapeutic and / or a targeted therapy agent are administered in separate pharmaceutical compositions. In some embodiments, a compound represented by the structure of Formula (23) and cisplatin are administered in separate pharmaceutical compositions. In some embodiments, a compound represented by the structure of Formula (23) and sorafenib are administered in separate pharmaceutical compositions.

[0214]

[0185] In some embodiments, the compounds of the invention are administered simultaneously. In some embodiments, a compound represented by the structure of Formula (II) and a chemotherapeutic and / or a targeted therapy agent are administered simultaneously. In some embodiments, a compound represented by the structure of Formula (23) and cisplatin are administered simultaneously. In some embodiments, a compound represented by the structure of Formula (23) and sorafenib are administered simultaneously.

[0215]

[0186] In some embodiments, the compounds of the invention are administered sequentially, in any order. In some embodiments, a compound represented by the structure of Formula (II) and a chemotherapeutic and / or a targeted therapy agent are administered sequentially, in any order. In some embodiments, a compound represented by the structure of Formula (23) and cisplatin are administered sequentially, in any order. In some embodiments, a compound represented by the structure of Formula (23) and sorafenib are administered sequentially, in any order.

[0216]

[0187] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, intravenous, intradermal, subcutaneous, oral, inhalation, transdermal, topical, intranasal, transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0217]

[0188] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0218]

[0189] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0190] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0219]

[0191] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0220]

[0192] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished using nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0221]

[0193] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0222]

[0194] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, poly glycolic acid, collagen, poly orthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers.

[0223]

[0195] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention is dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0224] Modes of Administration

[0225]

[0196] In some embodiments, the compositions as described herein, e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and / or targeted therapy agent, cisplatin, and / or sorafenib are administered via parenteral administration. In some embodiments, the compositions as described herein, e.g. the compositions as described herein, e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered via intravenous administration. In some embodiments, the compositions as described herein, e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered via oral administration. In some embodiments, the compositions as described herein, e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered via rectal administration.

[0226]

[0197] In some embodiments, the compositions as described herein, e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered via intranasal administration. In some embodiments, the compositions as described herein, e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered via topical administration. In some embodiments, the compositions as described herein, e.g. the composition of Formula (II), the composition of Formula (23), the chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered via administration by inhalation.

[0198] In some embodiments, the compositions are administered directly to the tumor site. In some embodiments, the administration comprises intratumoral injection, the implantation of a drug delivery device, or targeted drug-eluting nanoparticles. An artisan would appreciate that localized administration minimizes systemic exposure, potentially reducing side effects and improving the therapeutic index.

[0227]

[0199] It will be appreciated that administration of therapeutic entities in accordance with the invention will be with suitable carriers, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed, Mack Publishing Company, Easton, PA (1975)), particularly Chapter 87 by Blaug, Seymour, therein. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as Lipofectin™), DNA conjugates, anhydrous absorption pastes, oil- in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. Any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present invention, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. “Pharmaceutical excipient development: the need for preclinical guidance.” Regul. Toxicol Pharmacol. 32(2):210-8 (2000), Wang W. “Lyophilization and development of solid protein pharmaceuticals.” Int. J. Pharm. 203(1-2): 1- 60 (2000), Charman WN “Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts.” J Pharm Sci. 89(8): 967- 78 (2000), Powell et al. “Compendium of excipients for parenteral formulations” PDA J Pharm Sci Technol. 52:238-311 (1998) and the citations therein for additional information related to formulations, excipients and carriers well known to pharmaceutical chemists.

[0228]

[0200] A therapeutic regimen is carried out by identifying a subject, e g., a human patient suffering from (or at risk of developing) a malignancy, using standard methods. Efficaciousness of treatment is determined in association with any known method for cancer monitoring. Alleviation of one or more symptoms of the condition indicates a clinical benefit.

[0229]

[0201] In some embodiments, the compositions of the invention are administered at intermittent dosing schedules or adaptive dosing regimens, allowing for flexibility in treatment based on the subject's response to therapy.

[0202] In some embodiments, the compounds disclosed herein are administered with a sequential or phased administration strategy, in stages with defined intervals. This approach could be beneficial in managing side effects, optimizing treatment response, and potentially delaying or preventing the development of drug resistance.

[0230]

[0203] In some embodiments, the compounds disclosed herein are administered by continuous infusion techniques, thus allowing prolonged drug exposure. This continuous administration may be facilitated through implantable devices, wearable pumps, or other infusion systems, maintaining a consistent therapeutic drug concentration over an extended period.

[0231]

[0204] In some embodiments, a compound of Formula (II), a compound of Formula (23), a chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered by a single route. In some embodiments, a compound of Formula (23), a chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered by different routes . In some embodiments, a compound of Formula (23), a chemotherapeutic and / or a targeted therapy agent, cisplatin, and / or sorafenib are administered at different administration regimes. Kits

[0232]

[0205] In some embodiments, provided herein is a kit comprising (a) a compound represented by the structure of Formula (II) or a pharmaceutically acceptable salt thereof; and (b) a chemotherapeutic and / or a targeted therapy agent or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a kit comprising (a) compound of Formula (23) or a pharmaceutically acceptable salt thereof; and (b) a chemotherapeutic and / or a targeted therapy agent or a pharmaceutically acceptable salt thereof.

[0233]

[0206] In some embodiments, provided herein is a kit comprising (a) compound of Formula (23) or a pharmaceutically acceptable salt thereof; and (b) cisplatin or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a kit comprising (a) compound of Formula (23) or a pharmaceutically acceptable salt thereof; and (b) sorafenib or a pharmaceutically acceptable salt thereof.

[0234]

[0207] In some embodiments, the kit comprises bottles, vials, bags and syringes. In one embodiment, the compositions of Formula (II), the compound of Formula (23), the chemotherapeutic and / or targeted therapy agent, the cisplatin, or the sorafenib are provided in pre-filled syringes or containers for convenient and accurate dosage delivery. In further embodiments, the kit further comprises a package insert comprising instructions for using the composition. In some embodiments, the formulations in the kit are tailored for oral, injectable, or other appropriate routes of administration.

[0208] The container may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or poly olefin), or metal alloy (such as stainless steel or hastelloy). In particular, the kit may contain packaging features that enhance stability and shelf life of the drug. This may involve specialized packaging materials, storage conditions, or protective measures to preserve the integrity of the pharmaceutical composition. Additionally, the kit may include information regarding proper storage and handling.

[0235]

[0209] In some embodiments, the kit comprises means for monitoring the patient's response to the drug treatment, such as diagnostic tools, test kits, or instructions for regular check-ups. This embodiment facilitates personalized medicine by tailoring the drug administration based on the patient's individual characteristics and response to therapy, thereby optimizing treatment outcomes.

[0236]

[0210] In some embodiments, the kit comprises drug formulations and administration methods or tools designed with specific patient populations in mind, thus tailoring drug formulations and administration methods to accommodate a specific medical need, as pediatric version or geriatric needs.

[0237]

[0211] In some embodiments, the article of manufacture or kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some embodiments, the article of manufacture further includes one or more of another agent (e.g., a chemotherapeutic, a targeted therapy agent, and anti -neoplastic agent). Suitable containers for the one or more agent include, for example, bottles, vials, bags and syringes.

[0238]

[0212] Unless the context clearly requires otherwise, throughout the description and the claims, the terms “comprise,” “comprising,” and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”.

[0239]

[0213] Embodiments in the application that “comprise” a step or an element may, in other embodiments, “consist of’ the step or element, or in other embodiments, may “consist essentially of’ the step or element. In some embodiments, the term “consisting essentially of’ is to be interpreted to include the listed elements or steps, and any additional components or steps that do not affect the basic nature of the invention. In some embodiments, the term “consisting of’ is to be interpreted to include only the listed elements.

[0214] Words using the singular or plural number also include the plural or singular number, respectively. Additionally, the words “herein,” “above,” and “below” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of this application. As used herein, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise.

[0240] EXAMPLES

[0241]

[0215] Generally, the nomenclature used herein, and the laboratory procedures utilized in the present invention include chemical, molecular, biochemical, and cell biology techniques. Such techniques are thoroughly explained in the literature. See, for example, "Molecular Cloning: A laboratory Manual" Sambrook et al., (1989); "Current Protocols in Molecular Biology" Volumes I-III Ausubel, R. M., ed. (1994); "Cell Biology: A Laboratory Handbook", Volumes I-III Cellis, J. E., ed. (1994); The Organic Chemistry of Biological Pathways by John McMurry and Tadhg Begley (Roberts and Company, 2005); Organic Chemistry of Enzyme-Catalyzed Reactions by Richard Silverman (Academic Press, 2002); Organic Chemistry (6th Edition) by Leroy "Skip" G Wade; Organic Chemistry by T. W. Graham Solomons and, Craig Fryhle.

[0242]

[0216] A compound of Formula (23) can be represented as:

[0243] EXAMPLE 1: Compound (23) inhibition of viability and proliferation of liver cancer cells is dose-dependent

[0244]

[0217] Objective: to study and quantitate the effect of Compound (23) on cancer cells.

[0245]

[0218] Methods: the hepatocellular carcinoma cancer cell line HepG2 was used. Cells were added to wells (10,000 / well) in BIOMIMESYS® 3D matrix formed by a crosslinking reaction of hydrosoluble modified hyaluronic acid and other matrix components with ADH (adipic acid dihydrazide) to mimic the extracellular matrix (ECM).

[0246]

[0219] Cells were treated with increasing concentrations of Compound (23) and after 72 hr, cells were tested for proliferation using EdU staining. Viability was determined by DRAQ7 staining. Following fixation and permeabilization, anti-phospho histone H3 stain was used as an additional way to determine proliferation and Hoechst was used to stain nuclei.

[0247]

[0220] Results: Compound (23) induced a dose-dependent decrease in the number of live cells. Further, Compound (23) dose-dependently increased the number of dead cells, demonstrating an increase in cell death. The drug effect started at a low concentration of 10 nM and reached a 40% decrease in total cell number at 1000 nM, with less than 30% live cell compared with untreated control cells (Figure 1).

[0248] EXAMPLE 2: Synergism of Compound (23) and targeted therapy anti-cancer drugs

[0249]

[0221] Objective: to quantitatively study the interaction between Compound (23) and the targeted therapy sorafenib.

[0250] Determining ECso values for cell viability and cell proliferation for sorafenib and for Compound (23)

[0251]

[0222] Methods: The ECso of sorafenib for cell viability and the ECso of sorafenib for cell proliferation were determined by incubating HEPG2 cells for 72 hours with increasing concentrations of sorafenib, followed by DRAQ7 staining for viability tests (Figure 2A, circles) and EdU staining for cell proliferation tests (Figure 2A, squares). The ECso of Compound (23) for cell viability and cell proliferation were also determined using DRAQ7 and EdU staining. ECso were calculated by extrapolating the sorafenib and Compound (23) values that result in a mean cell viability of 50% in Table 1 and Table 2, respectively.

[0252]

[0223] Results: Sorafenib had an ECso for cell viability of 9.7 pM (Figure 2A, circles, Table 1). Compound (23) had a ECso of >1 pM for cell viability (Table 2).

[0253] Table 1. Sorafenib effect on cell viability

[0254] Table 2. Compound (23) effect on cell viability

[0255] Determining the interaction between Compound (23) and sorafenib on for cell viability

[0224] Methods: To study the interaction between Compound (23) and sorafenib on cell viability, HEPG2 cells were incubated with sorafenib at its EC50 concentration of 9.7 pM (data not shown) or at about one third of its EC50 concentration (3 pM) in combination with Compound (23) at increasing concentrations (3-1000 nM) for 72 hours. Cell media was used as a control. After incubation, cells were evaluated for cell viability by DRAQ7 staining.

[0256]

[0225] Results: When combined, 3 pM sorafenib (< 1 / 3 of the EC50 of sorafenib for cell viability) and 400 nM of Compound (23) (<l / 2 of the EC50 of Compound (23) for cell viability) reduced cell viability by 50% (calculated by extrapolating the Compound (23) values in Table 3), indicating a synergistic effect.

[0257] Table 3. Compound (23) and sorafenib effect on cell viability

[0258]

[0226] Methods: The Combination Index (CI) was calculated to assess the interaction between the two drugs, by measuring the ratio between the concentration of each drug when used in combination and alone for a given effect (in this case EC50). A CI below 1 is indicative of synergism.

[0259]

[0227] Results: Based on the above experiments, the combination index (CI) of Compound (23) and sorafenib was calculated to be 0.709, surprisingly indicating that there is synergism between Compound (23) and sorafenib. .

[0260] 9.7 M >1000 nM

[0261]

[0228] Unexpectedly, when Compound (23) was combined with sorafenib, a strong synergistic anti -cancer effect was observed.

[0262] EXAMPLE 3: Synergism of Compound (23) and chemotherapeutics

[0263]

[0229] Objective: to quantitatively study the interaction between Compound (23) and chemotherapeutics, using the chemotherapeutic cisplatin. Determining ECso value for cell viability and cell proliferation for cisplatin and for Compound (23)

[0264]

[0230] Methods: The EC50 of cisplatin for cell viability and the ECso of sorafenib for cell proliferation were determined by incubating HEPG2 cells for 72 hours with increasing concentrations of cisplatin, followed by DRAQ7 staining for viability tests (Figure 2B, circles) and EdU staining for cell proliferation tests (Figure 2B, squares). The ECso of Compound (23) for cell viability and cell proliferation were also determined using DRAQ7 and EdU staining. ECso were calculated by extrapolating the cisplatin and Compound (23) values that result in a mean cell viability of 50% in Table 4 and Table 5, respectively.

[0265]

[0231] Results: Cisplatin had a ECso of 100 pM for cell viability (Table 4), and Compound (23) had a ECso of 300 nM for cell viability (Table 5).

[0266] Table 4. Cisplatin effect on cell viability

[0267] Table 5. Compound (23) effect on cell viability

[0268] Determining the interaction between Compound (23) and cisplatin on for cell viability

[0269]

[0232] Methods: To study the interaction between Compound (23) and cisplatin on cell viability, HEPG2 cells were incubated with cisplatin at its ECso concentration for proliferation (15 pM, Figure 2B) or at one third of its proliferation ECso concentration (5 pM) in combination with Compound (23) at increasing concentrations (3-1000 nM) for 72 hours. Cell media was used as a control. After incubation, cells were evaluated for cell proliferation by EdU staining.

[0270]

[0233] Results: When combined, 5 pM cisplatin (1 / 20 of the ECso of cisplatin for cell viability) and 200 nM of Compound (23) (2 / 3 of the ECso of Compound (23) for cell viability) reduced cell viability by 50% (calculated by extrapolating the Compound (23) values in Table 6). Table 6. Compound (23) and cisplatin effect on cell viability

[0271]

[0234] Methods: The Combination Index (CI) was calculated to assess the interaction between the two drugs, by measuring the ratio between the concentration of each drug when used in combination and alone for a given effect (in this case ECso). A CI below 1 is indicative of synergism.

[0272]

[0235] Results: Based on the above experiments, the combination index (CI) of Compound (23) and cisplatin was calculated to be 0.71, indicating the synergism between Compound (23) and cisplatin.

[0273] 5 pM 200 nM

[0274] CI = - - - + - = 0.71

[0275] 100 pM 300 nM

[0276] Conclusions from Examples 1-3

[0277]

[0236] Compound (23) represents a breakthrough technology that uniquely interferes with the binding of hexokinase 2 to the VDAC1 mitochondrial channel in cancer cells without affecting hexokinase 1 in normal cells. This allows cancer-specific treatment that is both effective and safe. Moreover Compound (23) reduces the formation of Lactate in the tumor microenvironment. In this study, we demonstrated that a chemotherapy drug (cisplatin) and a targeted therapy drug (Sorafenib) can induce strong anti-tumor effects when used at its ECso or even lower in combination with Compound (23). The combination of Compound (23) with other treatments has the potential to reduce drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumor growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis. Surprisingly, we have found that the combination of compound (23) with cisplatin and with Sorafenib, which have two completely different modes of action, lead to a synergistic effect on viability of the cancer cells. EXAMPLE 4: Synergism of Compound (23) and chemotherapeutics in vivo

[0278]

[0237] Objective: to quantitatively study the interaction between Compound (23) and the chemotherapeutic cisplatin in a colorectal cancer syngeneic mice model.

[0279]

[0238] Methods: A colorectal cancer syngeneic mice model that retains fully intact immune systems was used. BALB / c derived CT-26 (Colon Tumor #26) cells were grown in culture medium until reaching 80% confluence. Cells were collected and resuspended at lxlOA7 cells / ml, live cells were > 90%.

[0280]

[0239] 0. 1 ml (lxlOA6 cells) of CT-26 cells were injected SC in the right flank region of 8- 10 weeks old BALB / c females. When tumor size reached 50mm2, mice were randomized into 6 groups of 10 mice with a unified average tumor size. The six groups were:

[0281] • vehicle (group 1; control),

[0282] • cisplatin 0.5 mg / kg (group 2),

[0283] • cisplatin 0.5 mg / kg + Compound (23) 400 mg / kg (group 3),

[0284] • cisplatin 1 mg / kg (group 4),

[0285] • cisplatin 1 mg / kg + Compound (23) 400 mg / kg (group 5), and

[0286] • Compound (23) 400 mg / kg (group 6).

[0287]

[0240] Mice were treated with cisplatin twice a week, and / or with Compound (23) daily. The doses and routes of administration for each therapeutic are detailed in Table 7.

[0288] Table 7. Combination of cisplatin and Compound (23) in the treatment of colon cancer.

[0289]

[0241] Tumor size was measured every two days according to the formula: Tumor size = A x B2, where A is the length (the long dimension of the tumor), B is the width, and tumor size is measured in mm3. In addition, body weight, behaviour, and clinical signs were evaluated every two days, and food and water consumption were monitored and recorded. An animal was sacrificed once its tumor grew to 1,800mm2or greater or once it lost >20% of its body weight.

[0290]

[0242] Tumor growth (without administration of the therapeutic compounds), Tumor Growth Inhibition (TGI%) as a result of administration of compounds, and the survival curve were calculated for each treatment group. After sacrifice, the tumor was removed from each animal and fixated in formalin. Aliquots were retained for further tests, which will include analysis of the amount and activity of markers of infiltrated immune cells (Neutrophils, NK, CD4 and CD8 T-cells, etc). The ratio of CD4 T effector / Treg, as well as macrophages and their Ml and M2 markers, concentration of lactate in the tumor, and the tumor micro-environment will also be analysed.

[0291] Results

[0292] Comparison of TGI between treatment groups

[0293]

[0243] Tumor size is presented in Figure 3 through day 22 of treatment, which was the first day that mice in the control untreated mice group died. Data from cisplatin at 1 mg / kg alone, Compound (23) alone, 1 mg / kg cisplatin + Compound (23), and the control untreated group is presented. The group of mice treated with the combination treatment of cisplatin (1 mg / kg) and Compound (23) (400 mg / kg) had the strongest inhibition of tumor expansion (Figure 3), with a 35.1% inhibition of tumor growth (TGI). Treatment of animals with Compound (23) alone inhibited tumor growth more effectively than treatment with cisplatin alone. Cisplatin treatment alone at the lower dose of 0.5 mg / kg demonstrated minor effects at day 22 (data not shown). Effectiveness of treatments compared to control groups for TGI

[0294]

[0244] We continued to monitor the tumor size in the different treatment groups compared to the control untreated group and the results at treatment day 38 are shown in Figures 4A-4E. A statistically significant reduction of tumor size was found in group 3 (cisplatin 0.5 mg / kg and Compound (23)), group 4 (cisplatin 1 mg / kg) and group 5 (cisplatin 1 mg / kg and

[0295] Compound (23)).

[0296] A synergistic effect of combination therapy with cisplatin and Compound (23)

[0297]

[0245] Treatment of mice with a combination of cisplatin (1 mg / kg) and Compound (23) (400 mg / kg) (Table 8, “% reduction” column, underlined value) had a greater effect on tumor reduction than the sum of the effects of each drug administered alone (Table 8, right hand column) after 19, 38 and 47 days of treatment.

[0298] Table 8. Synergistic effect of combination therapy was demonstrated on Days 19, 38, and 47 of treatment

[0299] Survival Curve

[0300]

[0246] A survival curve reveals the strong effect of the combined treatment with 1 mg / kg of cisplatin with 400 mg / kg of Compound (23), relative to control untreated group (Figure 5). The control group has a median survival of 26 days, while the cisplatin 1 mg / kg with Compound (23) treated group had a median survival of 45 days, which represents a more than 70% elongation of median survival. These data provide evidence in an in vivo model that combination treatment increases survival of subjects and also indicates that the treatment will have fewer adverse side effects than existing treatments, because a lower dosage of cisplatin (1 mg / kg) is needed when combined with Compound (23). The group treated with 1 mg / kg dosage of cisplatin as a monotherapy had a median survival of only 31 days, compared to 45 days for the combination treatment.

[0301]

[0247] These findings indicate that combining cisplatin, a standard-of-care therapy, with Compound (23) which has a strong safety profile and excellent efficacy on cancer cells, has the potential to provide a safer and more effective treatment for cancer patients. Furthermore, reducing the dosage of chemotherapy or other standard treatments could minimize adverse effects, thereby enhancing patients' quality of life. This data provides additional evidence that the combination of Compound (23) with cisplatin has a synergistic effect. These data are consistent with the studies described in Examples 1-3, which demonstrated a synergistic effect of Compound (23) both with cisplatin and Sorafenib on a 3D organoid model of human liver cancer cells. Data showing that Compound (23) modifies the tumor micro-environment and induces an immunological response provides support for the assertion that Compound (23) may be complementary and / or synergetic to other chemotherapeutical or immunological drug.

Claims

CLAIMS1. A combination for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said combination comprising:(a) a compound represented by the structure of Formula (II):whereinU and Z are each independently N or CH;X is O, NH, S, or a bond;Y is CH2, C=O, or C=S;R1is aryl, heteroaryl, or C(=O)-ORa, wherein aryl and heteroaryl are each optionally substituted with one or more alkyl, arylalkyl, halogen, NO2, CN, OR4, NR5aR5b, or a combination thereof;R2and R3are each independently at each occurrence selected from the group consisting of halogen, NO2, CN, C1-C4 alkyl, OR4, and NR5aR5b;R4, Ra, R5a, and R5bare each independently hydrogen or C1-C4 alkyl; n is 0 or 1; m is 0, 1, or 2; p and q are each independently selected from 0, 1, 2, 3, and 4; or a pharmaceutically acceptable salt thereof; and(b) a chemotherapeutic, a targeted therapy agent, or a combination thereof.

2. The combination of any one of claims 1-9, wherein said compound is a compound of Formula (V):

3. The combination of claim 2, wherein Z is N.

4. The combination of claim 3, wherein said compound is:

5. The combination of claim 3, wherein said compound is:

6. The combination of any one of claims 1-5, wherein said compound is a compound of Formula (III):

7. The combination of claim 6, wherein said compound is a compound of Formula (IV):

8. The combination of claim 7, wherein X is O.

9. The combination of claim 8, wherein said compound is:

10. The combination of any one of claims 1-5, wherein said compound is a compound of Formula (VI):

11. The combination of claim 10, wherein said compound is:

12. The combination of any one of claims 1-11, wherein said chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an antitumor antibiotic, a hormonal agent, or a combination thereof.

13. The combination of claim 12, wherein said alkylating agent comprises cisplatin, Cyclophosphamide, Carboplatin, Etoposide, Melphalan, or a combination thereof; said antimetabolite comprises Methotrexate, 5 -fluorouracil (5-FU), Mercaptopurine, Cytosine arabinoside (Ara-C), Cladribine, or a combination thereof; said antitumor antibiotic comprises Actinomycin D, Dactinomycin, Doxorubicin, Bleomycin, Mitomycin C, or a combination thereof; said hormonal agent comprises Tamoxifen, Anastrozole, Letrozole, Exemestane, Fulvestrant, or a combination thereof;14. The combination of any one of claims 1-13, wherein said targeted therapy agent comprises Sorafenib, Trastuzumab, Erlotinib, Gefitinib, Imatinib, Rituximab, or a combination thereof; or wherein said targeted therapy agent comprises an immunotherapy.

15. The combination of claim 14, wherein said immunotherapy comprises Ipilimumab, Pembrolizumab, Nivolumab, Atezolizumab, Durvalumab, or a combination thereof.

16. A combination for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said combination comprising a compound represented by Formula (23):or a salt thereof; and (b) sorafenib or a salt thereof.

17. A combination for treating a cancer or other hyperproliferative disorder in a subject in need thereof, said combination comprising a compound represented by Formula (23):or a salt thereof; and (b) cisplatin or a salt thereof.

18. The combination of any one of claims 1-17, wherein treating a cancer comprises blocking cancer cell proliferation, inducing apoptosis in cancer cells, decreasing cancer cell viability, creating a pro-inflammatory environment within a tumor, or a combination thereof.

19. The combination of any one of claims 1-18, wherein said compound of Formula (II) and said chemotherapy and / or said targeted therapy agent are formulated for administration in the same pharmaceutical composition or in separate pharmaceutical compositions.

20. The combination of claim 19, wherein said compound of Formula (II) and said chemotherapy and / or said targeted therapy are formulated for administration simultaneously or sequentially, in any order.

21. The combination of any one of claims 1-20, wherein said compound of Formula (II) and / or said chemotherapy and / or said targeted therapy are formulated for administration via parenteral administration, intravenous administration, oral administration, rectal administration, intranasal administration, topical administration, or administration by inhalation.

22. The combination of any one of claims 1-21, wherein said cancer comprises a solid tumor or a non-solid tumor.

23. The combination of claim 22, wherein said wherein said solid tumor comprises colon cancer, cervical cancer, lung cancer, pancreatic cancer, breast cancer, liver cancer, skin cancer, melanoma, lymphoproliferative disorders, ovarian cancer, prostate cancer, endometrial cancer, bone cancer, stomach cancer, cancer of the thyroid, head and neck cancer, cancer of the central nervous system, cancer of the peripheral nervous system, kidney cancer, hepatocellular carcinoma, hepatoma, hepatoblastoma,rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, ganglioblastoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, Ewing’s tumor, leimyosarcoma, rhabdotheliosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, adenocarcinoma, renal cell carcinoma, hypernephroma, hypemephroid adenocarcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, testicular tumor, lung carcinoma, bladder carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, retinoblastoma, neuroblastoma, colon carcinoma, rectal carcinoma, colorectal carcinoma, hematopoietic or hematologic malignancies, or metastases thereof.

24. The combination of claim 22, wherein said non-solid tumor comprises a hematologic cancer, acute myelogenous leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, cutaneous T-cell lymphoma, or metastases thereof.

25. A compound for increasing the anti-tumor effect of sorafenib or cisplatin in a subject, wherein said compound is represented by Formula (23):or a pharmaceutically acceptable salt thereof.

26. A combination for reducing the viability of tumor cells in a subject having a tumor, comprising a compound represented by Formula (23):or a salt thereof; and (b) sorafenib or cisplatin, or a salt thereof.

27. A pharmaceutical composition comprising:(a) a compound represented by Formula (23):(b) a pharmaceutically acceptable carrier; and(c) a compound selected from (i) sorafenib or pharmaceutically acceptable salts thereof and (ii) cisplatin or pharmaceutically acceptable salts thereof.

28. The pharmaceutical composition of claim 27, wherein said composition is formulated for parenteral, oral, rectal, intranasal, topical, inhalation, intravenous, subcutaneous, intraperitoneal, intraarterial, transdermal, or intramuscular administration.

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