Methods and compositions to inhibit tribbles 2 for cancer therapy

Abstract

Compositions and treatment methods for cancer, such as enzalutamide resistant cancers, using one or more alternatives to daclatasvir (DCV). DCV has been shown to inhibit the Tribbles homolog 2 (TRIB2) pseudokinase encoded in humans by the TRIB2 gene, but more potent compounds are described herein that bind and inhibit the TRIB2 pseudokinase with greater affinity. TRIB2 is a target for several types of very aggressive cancers, such as castration resistant prostate cancer (CRPC), small cell lung cancer (SCLC), pancreatic neuroendocrine cancer (PNEC), triple negative breast cancer (TNBC), sarcomatoid kidney cancer, and melanoma.

Description

METHODS AND COMPOSITIONS TO INHIBIT TRIBBLES 2 FOR CANCERTHERAPYTECHNICAL FIELD

[0001] The present disclosure relates to methods and compositions for treating cancer, more particularly, for cancers that cause the expression of higher levels of Tribbles homolog 2 (TRIB2), relative to non-cancer cells.BACKGROUND

[0002] Enzalutamide is an androgen receptor inhibitor used for the treatment of prostate cancer. Although patients show initial response to treatment, resistance to enzalutamide can develop. Enzalutamide-resistant prostate cancer (ERPC) is an incurable, end-stage disease. ERPC is one of the deadliest forms of malignancies and can be the cause of excruciating pain and suffering because of bone metastasis and eventual death to people in the United States, New Zealand, Barbados. Jamaica, Australia, and Europe, for example.

[0003] The Tribbles 2 (TRIB2) pseudokinase is over-expressed and can play a critical role in the survival of Enzalutamide-resistant type prostate cancer (ERPC) cells, and inhibition of TRIB2 by shRNA can kill ERPC cells by triggering apoptosis. Thus, TRIB2 has emerged as a new molecular target for ERPC. and effective inhibitors of TRIB2 can be developed as an effective therapy for ERPC.

[0004] The FDA-approved drug Daclatasvir has been shown to help with inhibition of the TRIB2 protein, as described in WO 2021 / 248093, assigned to the present Applicant, and incorporated by reference herein in its entirety. However, new compositions may be more effective in inhibiting TRIB2 and promoting anti-tumor effects. This can be beneficial in treating a wide array of cancers, particularly those cancer types in which TRIB2 is overexpressed.SUMMARY

[0005] In accordance with one embodiment, there is provided a composition for treating cancer, comprising a therapeutically effective amount of a compound selected from Formula (1), Formula (2), or a combination of Formula (1) and Formula (2):or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R isXI iswherein B is a terphenyl group.

[0006] In some embodiments, the terphenyl group is an ortho-terphenyl group, and in some implementations, the compound comprises a therapeutically effective amount of Formula (1), and Formula (1) is:

[0007] The compound can comprise a therapeutically effective amount of Formula(2). and Formula (2) is:

[0008] In some embodiments, Formula (2) is:

[0009] In accordance with one embodiment, there is provided a composition for treating cancer, comprising a therapeutically effective amount of:or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein A is a non-oxygenated pyrrolidinyl imidazole or a pyrrolidinyl imidazole having three or fewer nitrogen atoms.

[0010] In some embodiments, A is 2-(2 -pyrrolidinyl)- IH-imidazole.

[0011] The cancer may be an enzalutamide-resistant cancer and / or a castration resistant prostate cancer (CRPC), small cell lung cancer (SCLC), pancreatic neuroendocrine cancer (PNEC), triple negative breast cancer (TNBC), sarcomatoid kidney cancer, or melanoma.

[0012] Some embodiments are directed to a method of treating cancer, comprising administering one or more of the above compositions to a subject in need thereof.

[0013] The method can inhibit Tribbles homolog 2 (TRIB2) pseudokinase, and in some embodiments, the compound of the composition is configured to bind with Ser-133 and Val-92 of TRIB2, or more particularly, hydrogen bond with Ser-133 and Val-92 of TRIB2. The method may also include administering one or more of Enzalutamide, Apalutamide, Darolutamide, and abiraterone in a therapeutically effective amount.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Illustrative embodiments will hereinafter be described in conjunction with the following figures, wherein like numerals denote like elements, and wherein:

[0015] FIG. 1 illustrates cell morphology, comparing daclatasvir (DCV) treatment with H027-4038C;

[0016] FIG. 2 is a Western blot of protein data, comparing DCV treatment with 14027- 4038C;

[0017] FIG. 3 is a thermal shift assay, comparing DCV treatment with H027-4038C;

[0018] FIG. 4 illustrates the 3-dimensional orientation of DCV in the active site of TRIB2;

[0019] FIG. 5 shows the polar contacts established between DCV and TRIB2;

[0020] FIG. 6 shows binding pocket residues of TRIB2 with DCV superimposed;

[0021] FIG. 7 illustrates the 3-dimensional orientation of H027-4038C in the active site of TRIB2;

[0022] FIG. 8 shows the polar contacts established between H027-4038C and TRIB2; and

[0023] FIG. 9 shows binding pocket residues of TRIB2 with H027-4038C superimposed.DETAILED DESCRIPTION Definitions

[0050] The term "combination" as used herein refers to the administration of two or more therapeutic agents. This term encompasses simultaneous, separate and / or sequential administration of therapeutic agents.

[0051] A " counterpart non-cancer cell" as used herein is a normal, non-transformed cell that is used as a reference to a cancer cell and is typically derived from the same tissue or progenitor cell as the cancer cell to which it is being compared. By contrast, a cell that has undergone malignant transformation is a cancer cell.

[0052] As used herein, the phrase "derived from," as it relates to a cell, refers to the entity7and / or location from which the cell originates. For example, a cell may be derived from a subject in that said cell is found in or taken from said subject. A cell may be derived from a subject by any methods known in the art, including collection of one or more cells by biopsy or by taking a blood sample. As another example, a cell may be derived from a specific organ or tissue in a subject. In a subject with cancer, a cancer cell may be derived from the subject, for instance, by methods including tumor biopsy. As another example, a cell that is differentiated may be derived from a less differentiated cell, such as a progenitor cell.

[0053] The term "express" as it relates to a cell or population of cells refers to gene expression or protein production by the cell or population of cells. As used herein, "express" or "expression" can refer to one or more of the following: (1) production of an RNA template from a DNA sequence (e.g.. by transcription); (2) processing of an RNA transcript (e.g., bysplicing, editing, 5' cap formation, and / or 3' end processing); (3) translation of an RNA into a polypeptide or protein; (4) folding of a polypeptide or protein; and (5) post-translational modification of a polypeptide or protein. In some embodiments of the present disclosure, a protein may be over-expressed or expressed at higher levels in different cells. In some embodiments, a protein (e g., TRIB2) may be over-expressed or expressed at higher levels in a cancer cell compared to a non-cancer cell, such as a counterpart non-cancer cell.

[0054] The terms "inhibit" or "inhibition of’ mean to reduce or block by a measurable amount, or to reduce or block entirety. The term inhibition as used herein can refer to an inhibition or reduction of at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

[0055] The term "prevention" as used herein refers to a prophylactic approach intended to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

[0056] As used herein, the term "subject" is intended to include human and non-human animals. The terms "subject" and "patient" are used interchangeably and can refer to human patients, as well as non-human primates or experimental animals such as rabbits, dogs, cats, rats, mice, and other animals. Preferred subjects of the present disclosure include mammals, or more particularly, human patients in need of a treatment for a disease or disorder. The compositions and methods described herein are suitable for the treatment of a subj ect having a disease or disorder that benefits from inhibition of Tribbles homolog 2 (TRIB2). A subject of the present disclosure may be a patient suffering from cancer, such as prostate cancer, lung cancer, pancreatic cancer, breast cancer, kidney cancer, and / or melanoma. In a particular embodiment, the compositions and methods described herein are particularly suitable for treatment of lung cancer, and / or prostate cancer, such as enzalutamide-resistant prostate cancer (ERPC).

[0057] As used herein, the term "therapeutically effective amount" refers to an amount that is sufficient to confer a desired biological or therapeutic result. A therapeutically effective amount of a therapeutic agent can treat, improve symptoms of, prevent, and / or delay the onset of a disease, disorder, and / or condition. In reference to cancer, a therapeutically effective amount may comprise an amount sufficient to cause a tumor to shrink and / or suppress tumor growth. A therapeutically effective amount may prevent or delay unwanted cell proliferation, delay tumor development, ameliorate symptoms, prolong survival or induce stabilization of the cancer or tumor. A therapeutically effective amount of a therapeutic agent or combination of therapeutic agents may result in one or more of the following: (i) reduce the number of cancer cells; (ii) reduce tumor size; (iii) inhibit, slow-, or stop cancer cell infiltration into peripheral organs; (iv) inhibit (i.e., slow' to some extent and preferably stop) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay occurrence and / or recurrence of tumor; and / or (vii) relieve to some extent one or more of the symptoms associated with the cancer. A therapeutically effective amount can be administered in one or more administrations. In some embodiments, a therapeutically effective amount is provided in a single dose. In some embodiments, a therapeutically effective amount is administered in a dosage regimen comprising a plurality of doses. One of ordinary skill in the art would be able to determine a therapeutically effective amount to treat a subject based on such factors as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0058] As used herein, the terms "treatment" or "treating” refer to an approach for obtaining a beneficial or desired result, preferably a beneficial or desired clinical result. Suchbeneficial or desired clinical results include, but are not limited to: (1) curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, interfering with, or affecting a condition (e.g., a disease), the symptoms of the condition, or the biological manifestations of the condition; (2) interfering with one or more points in the biological cascade that leads to or is responsible for the condition; (3) preventing, delaying, or slowing the onset or progression of the symptoms, complications, biological manifestations, and / or biochemical indicia of a disease or condition; or (4) otherwise arresting or inhibiting further development of the disease, condition, or disorder. The compositions and methods of the present disclosure are suitable for obtaining beneficial or desired results such as reducing the proliferation of (or destroying) cancerous cells or other diseased cells, reducing metastasis of cancerous cells found in cancers, shrinking the size of the tumor, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and / or prolonging survival of treatment subjects. Treatment can include administration of one or more therapeutic agents with the purpose to achieve the beneficial or desired results described herein.

[0059] The terms "tumor" and "cancer" are used interchangeably and refer to a cell or population of cells whose growth, proliferation or survival is greater than growth, proliferation or survival of a normal counterpart cell. The cell or population of cells in a tumor or cancer possess abnormal growth, and typically the growth is uncontrolled. The term "malignancy" refers to the property of a tumor or cancer cell to have the ability to invade nearby tissue. The term "metastasis" refers to spread or dissemination of a tumor, cancer or neoplasia to other sites, locations or regions within the subject, in which the sites, locations or regions are distinct from the primary tumor or cancer.

[0060] The terms "resistant" or "resistance" as used herein refer to the state in which (i) a disease or condition in a subject, or (ii) a cell or population of cells characterized by having the properties of a disease or condition, does not respond to a specified treatment. A subject suffering from a disease or condition may have a disease or condition with primary resistance, which means that the disease or condition does not respond at all to treatment. Alternatively, a subject may have a disease or condition with secondary resistance, which means that the disease or condition initially responds to treatment but develops resistance later on. A cell or population of cells may also have primary7resistance or secondaryresistance. A cell can be modified to be resistant to a specific treatment for research purposes. As used in the present disclosure, resistance refers to a cancer cell or population of cancercells, either in isolation or in the context of a disease or condition in a subject suffering from the cancer, wherein the cancer cell or population of cancer cells do not respond to specified treatment.

[0061] As used herein, "about" means within acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation per the practice in the art. Alternatively, "about" can mean a range of up to 20%. When particular values are provided in the application and claims, unless otherwise stated, the meaning of "about" should be assumed to be within acceptable error range for that particular value.

[0062] As used herein, an "effective amount" is defined as the amount required to confer a therapeutic effect on the treated patient, and is typically determined based on age. surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See. e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" generally refers to a mammal, including a human.

[0063] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the subject's immune system, and can include any and all solvents, diluents, carriers, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, non-toxic, and does not interfere with the mechanism of action of the compounds described herein, or pharmaceutically acceptable salts thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329).

[0064] Preferably, the pharmaceutical acceptable excipient is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the compounds detailed herein, or pharmaceutically acceptable salts thereof, may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound. Pharmaceutically acceptable excipients include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterileinjectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the disclosure is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0065] The phrase "stable or chemically feasible," as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0066] The methods of treatment of the disclosure comprise administering a safe and effective amount of one or more compounds described herein or pharmaceutically-acceptable salts thereof to a subject in need thereof.

[0067] The terms ‘Tor example,'’ “for instance,’' “such as,” and “like,” and the verbs “comprising.” “having,” “including.” and their other verb forms, when used in conjunction with a listing of one or more compounds or other items, are each to be construed as open- ended, meaning that the listing is not to be considered as excluding other, additional compounds or items. Other terms are to be construed using their broadest reasonable meaning unless they are used in a context that requires a different interpretation. In addition, the term “and / or” is to be construed as an inclusive OR. Therefore, for example, the phrase “A, B, and / or C” is to be interpreted as covering all the following: “A”; “B”; “C”; “A and B”; “A and C “B and C”; and “A, B, and C”.

[0068] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Examples of isotopes that can be incorporated into one or more of the compounds of the present disclosure and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11 C, 13C, 14C, 15N, 170, 180, 3 IP, 32P. 35S, 18F, 36C1, 1231 and 1251.

[0069] The compounds of the present disclosure and pharmaceutically acceptable salts of the compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present disclosure, for example those into which radioactive isotopes, such as 3H and14C, are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated hydrogen (3H) and carbon- 14 (14C) isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (positron emission tomography), and 1251 isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium (2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the schemes and / or in the examples below, and substituting a readily available isotopically labeled reagent for a non-isotopically labelled reagent.

[0070] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure. "Isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties; for example (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. The structural difference may be in constitution (geometric isomers) or in the ability7to rotate the plane of polarized light (stereoisomers); for example, the R and S configurations for each asymmetric center. The compounds of the invention may contain one or more asymmetric centers, also referred to as chiral centers, and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. All such isomeric forms are included within the present invention, including mixtures thereof. Chiral centers may also be present in a substituent such as an alky l group.

[0071] Where the stereochemistry of a chiral center present in one or more of the compounds, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, compounds containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

[0072] Individual stereoisomers of one or more compounds which contain one or more asymmetric centers may be resolved by methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica witha bound chiral ligand or in the presence of a chiral solvent. The skilled artisan will appreciate that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0073] Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0074] Any numerical range disclosed herein encompasses the and lower limits and each intervening value, unless otherwise specified. Other than in working examples, or where otherwise indicated, numerical values (such as numbers expressing quantities of ingredients, reaction conditions) as used in the specification and claims are modified by the term "about". Accordingly, unless indicated to the contrary, such numbers are approximations that may vary depending upon the desired properties sought to be obtained. At the very7least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.

[0075] While the numerical parameters setting forth the scope of the disclosed subject matter are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in its respective testing measurements.

[0076] Unless defined otherwise, the meanings of technical and scientific terms as used herein are those commonly understood by one of ordinary skill in the art to which the disclosed subject matter belongs.Description

[0077] Daclatasvir (referred to synonymously herein as "DCV") is an FDA-approved, orally available antiviral compound commonly used in combination with other antiviral agents to treat hepatitis C virus (HCV) infection. DCV has the official IUPAC name: 4,4'- bis[2-((2S)-l-{(2S)-2- [(methoxycarbonyl)amino ]-3-methylbutanoyl }-2-pyrrolidinyl)-lH- imidazol-4-yl]-l, 1 '- biphenyl, CAS# 10091 19-64-5. The chemical formula for DCV is shown below-.

[0078] DCV has been shown to inhibit the Tribbles homolog 2 (TRIB2) pseudokinase encoded in humans by the TRIB2 gene, but more potent compounds are described herein that bind and inhibit the TRIB2 pseudokinase with greater affinity. TRIB2 belongs to the mammalian Tribbles family of serine / threonine pseudokinases (TRIBI, TRIB2, and TRIB3) that have a catalytically impaired pseudokinase domain and show very low or no phosphotransferase activity. TRIB proteins are thought to act as scaffold proteins that mediate the ubiquitylation and subsequent proteasomal degradation of substrate proteins. In addition to their roles in the context of protein stability, TRIB proteins are also recognized to modulate the activity of signaling pathways such as the canonical AKT pathway.

[0079] Dysregulation of TRIB2 has been linked to a variety of malignancies, including leukemia, melanoma, lung cancer, and liver cancer. However, despite being implicated as an oncogenic protein, there is a lack of target-validated small-molecule compounds available to better understand the oncogenic mechanisms of and treatment opportunities related to TRIB2.

[0080] In one embodiment, there is a composition for treating cancer, comprising a therapeutically effective amount of a compound selected from Formula (1), Formula (2), or a combination of Formula (1) and Formula (2). Formula (1) and Formula (2) are shown below.RFormula (1)Formula (2) including stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein R iswherein B is a terphenyl group.

[0081] In advantageous implementations, the compounds of Formula (1) and Formula(2) can bind and inhibit the TRIB2 pseudokinase with greater affinity, as detailed furtherbelow. The compounds and their structural analogs / derivatives also have the potential to be more effective in combination with standard anti-androgenic therapies (e.g., Enzalutamide, Apalutamide, Darolutamide. and abiraterone). or other clinically used anticancer modalities. Initial testing has shown that the compounds of Formula (1) and Formula (2) may be unexpectedly more effective than DCV in inhibiting TRIB2, while having a minimal impact on non-cancerous cells.

[0082] In another embodiment, the composition for treating cancer comprises a therapeutically effective amount of a compound according to Formula (3). Formula (3) is shown below-.Formula (3) including stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein A is a non-oxygenated pyrrolidinyl imidazole or a pyrrolidinyl imidazole having three or fewer nitrogen atoms. As detailed further below, this arrangement in the compound provides for a less polarized end group (A) as compared, for example, with DCV. This may help attribute to the improved binding affinity with TRIB2.

[0083] In one particularly advantageous example, A is 2-(2-pyrollidinyl)-lH- imidazole, such that one particular compound example for Formula (1) and Formula (3) is the following:

[0084] This particular compound may also be known as H027-4038C, which may be derived from DCV or an analog thereof. However, the structural differentiations betweenH027-4038C and DCV can improve treatment outcomes given the greater binding efficiencies of H027-4038C, as detailed further below.

[0085] In other advantageous embodiments, the composition includes Formula (2) compounds that are structurally analogous to the following:

[0086] In these embodiments of Formula (2), there is a terphenyl group which is structurally differentiated from DCV. As illustrated, the terphenyl group in these examples is an ortho-terphenyl group, which may result in a more compact molecular structure to improve binding affinity. Having the terphenyl group, and more particularly, the orthoterphenyl group towards the middle results in more hydrophobic groups in the middle to bind in the pocket of TRIB2. These compounds may also be known as H027-4127 and H027-4128 respectively (with H027-4127 above, H027-4128 below), and which may also be derived from DCV or an analog thereof.

[0087] In particular examples. H027-4038C, H027-4127, and H027-4128 are more potent analogs of DCV in decreasing the viability of Enzalutamide-resistant prostate cancer (ERPC) cells. Moreover, they have been shown to bind and inhibit the TRIB2 pseudokinase with greater affinity'. TRIB2 has been recently characterized as a novel target for several ty pes of very aggressive cancers, such as castration resistant prostate cancer (CRPC), small cell lung cancer (SCLC), pancreatic neuroendocrine cancer (PNEC), triple negative breast cancer (TNBC), sarcomatoid kidney cancer, and melanoma. Thus, these three newly found compounds and their structural analogs / derivatives may be more effective in combinationwith standard anti-androgenic therapies (such as Enzalutamide, Apalutamide, Darolutamide, and abiraterone), or other clinically used anticancer modalities. Based on recent results, these three compounds and their derivatives have the potential to be breakthrough treatments for the above mentioned advanced, therapy -resistant cancers for which no effective targeted therapies exist.

[0088] H027-4038C, H027-4127, and H027-4128 have been tested in a drug screening project in which it was found that they strongly inhibit TRIB2 in a luciferase fusion protein-based assay, which suggests that these three examples in particular may be new, more promising inhibitors of TRIB2. The effects of these compounds were observed on the morphology of Enzalutamide-resistant prostate cancer (ERPC) cells under microscope. The cancer cell viability’ was measured by MTS / PES mitochondrial dye-reduction assay. After in vitro testing, it was found that these compounds decrease the TRIB2 protein levels and induced rapid apoptotic death in human ERPC cells. Moreover, these compounds were found to have more minimal effects on normal, non-cancer cells under the same experimental conductions. This was an unexpected and remarkable finding, and thus, these three compounds in particular seem to be particularly promising as new anti-cancer agents against ERPC and other cancers where TRIB2 is overexpressed. Additionally, the compounds minimal affect to normal, non-cancer cells provides a significant technical advantage to selectively attack the cancer cells while sparing normal healthy cells which do not express TRIB2.

[0089] Even more particularly, H027-4038C has shown more promise as a cancer treatment. It has been shown that this compound in particular (see also Formula (1) and Formula (3) for example structurally similar compounds), are more soluble than DCV, which may help impart the increased ability to inhibit TRIB2. Accordingly, Formula (1) and Formula (3). and more particularly, H027-4038C may be even more effective at treating TRIB2 positive cancers, including but not limited to castration resistant prostate cancer (CRPC), small cell lung cancer (SCLC), pancreatic neuroendocrine cancer (PNEC), triple negative breast cancer (TNBC), sarcomatoid kidney cancer, and melanoma. In particular, H027-4038C has unexpectedly been shown to be two- to three- fold stronger than DCV at binding and inhibiting TRIB2.

[0090] To assess the potential treatment success of H027-4038C in particular, as compared with DCV, a cell viability analysis was performed. As shown in Table 1 below, a number of compounds were tested and 38C (referring to H027-4038C) had superior results at both a lOpM dose and a 20 pM dose, showing the lowest percentage of cell viability forEnzalutamide-resistant cells (LNCaP-ENR).

[0091] Table 1

[0092] Similarly. H027-4038C performed significantly better with respect to TRIB2 cells (LNCaP-TRIB2 cells) at various example dosage amounts, as shown in Table 2 below: Table 2

[0093] FIG. 1 shows a cell morphology comparison between DCV and H027-4038C in which various doses of each compound (e.g., 2 pM. 4 pM, and 8 pM) were used to treat TRIB2 positive cells. As shown in FIG. 1, H027-4038C performed significantly better than DCV at each dosage level, particularly at 4 pM and 8 pM. Additionally, apoptosis was induced at lower dosages compared with DCV. This may be at least partially due to the fact that H027-4038C is more bioavailable and has a stronger / tighter bond with TRIB2. Additionally, H027-4038C has been shown to be non-toxic to normal, non-cancerous cells, showing minimal impact on non-cancerous cells.

[0094] FIG. 2 shows a Western blot comparison of the impact of DCV and H027- 4038C on various proteins at various doses (e g., 4 pM and 8 pM). The impact on TRIB2 is substantial, and the other proteins are typically up-regulated or down-regulated by the presence of TRIB2. For example, pAKT-(S473) is a kinase regulated by TRIB2 downstream, and survivin is a pro-survival protein that is also typically upregulated by TRIB2. Accordingly, H027-4038C’s stronger impact also impacted the TRIB2 regulatory chain, thereby proving its enhanced efficacy over DCV. PARP Clv-PARP is cleaved during apoptosis so the increase with H027-4038C as compared with DCV shows increased amounts of cell death. Similarly, ATF3 is a tumor suppressant downregulated by TRIB2, so its expression is higher without TRIB2. as shown in FIG. 2, with H027-4038C having a greater impact on TRIB2 than DCV based on this finding.

[0095] FIG. 3 illustrates results of a thermal shift assay, showing that there is more TRIB2 denaturing / destabilization with H027-4038C as compared with DCV (and DMSO which is used as a control). The decrease in fluorescence is prominent, at least partially due to the fact that H027-4038C is able to denature and / or destabilize TRIB2 more effectively than DCV.

[0096] FIGS. 4-6 illustrate the molecular docking of DCV in the active site of TRIB2. The binding interaction energy score was calculated at -8.6. FIG. 4 shows the three- dimensional orientation of DCV in the active site of TRIB2. FIG. 5 show's the polar contacts established between the ligand and the protein. Glu-71, Ser-100, Ser-133, Glu-194, Glu-197, and Asp-198 residues of TRIB2 formed a hydrogen bond with the DCV. FIG. 6 shows the binding pocket residues 12, 14, 16, 18, 20 taking part in the hydrogen, hydrophobic, and vander Walls interactions.

[0097] FIGS. 7-9 illustrate the molecular docking of H027-4038C in the active site of TRIB2. The binding interaction energy score was calculated at -8.9. which is an improvement over DCV. FIG. 7 shows the three-dimensional orientation of H027-4038C in the active site of TRIB2. FIG. 8 shows the polar contacts established between the ligand and the protein. The Ser-133 and Val-92 residues of TRIB2 (see ref. nos. 22, 24, respectively) formed a hydrogen bond with H027-4038C. FIG. 6 shows the binding pocket residues 26, 28 taking part in the hydrogen, hydrophobic, and van der Walls interactions. The binding is tighter with Ser-133 and Val-91 residues, which along with the smaller size of H027-4038C, lends to the greater affinity of H027-4038C to inhibit TRIB2 as compared with DCV.

[0098] In some embodiments, the compositions may include other compounds besides those described, or it may be desirable to use the compositions having the compounds in combination with other therapeutic treatments. In one example, the compositions herein could be combined with enzalutamide, to van' the treatment targets and increase the synergistic effect (e.g., such treatment may not merely be additive, but may be even further improved given the variance in treatment targets).

[0099] In one aspect, the present disclosure provides a method of preventing or treating cancer in a subject in need thereof, said method comprising administering a therapeutically effective amount of one or more compounds in accordance with Formulas (1). (2), and (3) to a subject suffering from cancer. In some embodiments, the present disclosure provides methods of preventing or treating cancer that over-expresses or has higher levels of expression of TRIB2. In some embodiments, the present disclosure provides methods of preventing or treating prostate cancer or other TRIB2 positive cancers. Prostate cancer that may be treated according to the methods of the present disclosure include cancer that has previously been treated with androgen deprivation therapy (ADT) (e.g., enzalutamide), cancer that is resistant to ADT, or cancer that has previously been treated with ADT and developed resistance to ADT treatment. In some embodiments, one or more of the compounds can be used in accordance with the present disclosure to treat enzalutamide-resistant prostate cancer (ERPC).

[0100] In some embodiments, the compounds selectively attack cancer cells (e.g., cancer cells that over-express TRIB2 and / or prostate cancer cells). In some embodiments, the compounds minimally affect non-cancer cells. In some embodiments, the compounds minimally affect cells which do not express or express low levels of TRIB2.

[0101] In some embodiments, compositions and methods of the present disclosuremay be useful for reducing a tumor volume or burden in a subject, inhibiting tumor grow th in a subject, or reducing the levels of TRIB2 protein in a tumor.

[0102] The compounds in accordance with Formulas (1), (2), and / or (3). or pharmaceutically acceptable salts thereof, can be formulated as pharmaceutical compositions comprising a therapeutically or prophylactically effective amount of the compound or salt, and one or more pharmaceutically compatible (acceptable) ingredients. In some aspects, pharmaceutical compositions containing one or more of the compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical excipients are provided in which an effective amount of one or more of the compounds or salts, are in admixture with the excipients, suitable for administration to a subject, and advantageously, a mammal. In preferred aspects, the compounds, or pharmaceutically acceptable salts thereof, are formulated for administration to a human. The present disclosure provides a pharmaceutical composition comprising one or more of the compounds, or pharmaceutically acceptable salt thereof, formulated for administration to a human subject in need thereof. The formulated composition comprising one or more of the compounds, or pharmaceutically acceptable salts thereof, will generally comprise one or more pharmaceutically compatible (acceptable) ingredients.

[0103] Example pharmaceutical or non-pharmaceutical compositions typically include one or more carriers (e.g., sterile liquids, such as w ater and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like). Water is a more typical earner when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable excipients include, for example, amino acids, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. The composition, if desired, can also contain minor amounts of w etting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. Such compositions will typically contain a therapeutically effective amount of one or more of the compounds of Formulas (1), (2), and / or (3), or pharmaceutically acceptable salts thereof, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.The formulations correspond to the mode of administration.

[0104] The pharmaceutically acceptable carrier or vehicle can be particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) can be liquid, with the compositions being, for example, an oral syrup, flavored water, or injectable liquid.

[0105] When intended for oral administration, the composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.

[0106] As a solid composition for oral administration, the composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form. Such a solid composition typically contains one or more inert diluents. In addition, one or more of the following can be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, com starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent.

[0107] When the composition is in the form of a capsule, e.g., a gelatin capsule, it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or fatty oil.

[0108] The composition can be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension. The liquid can be useful for oral administration or for delivery by injection. When intended for oral administration, a composition can comprise one or more of a sweetening agent, preservatives, dye / colorant, and flavor enhancer. In some aspects, the composition is formulated into a powder and the end user mixes the power in aqueous solution for oral administration. In a composition for administration by injection (as described above), one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can also be included.

[0109] The composition and preparation of capsules are well known in the art. For example, capsules may be prepared from gelatin (e.g.. Type A, Type B). carrageenan (e.g., kappa, iota, lambda) and / or modified cellulose (e.g., hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate), and optionally one or more excipients such as oils (e.g., fish oil, olive oil, com oil, soybean oil, coconut oil, tri-, di- and monoglycerides), plasticizers (e.g.. glycerol, glycerin, sorbitol, polyethylene glycol, citric acid, citric acid esters such astri ethylcitrate, poly alcohols), co-solvents (e.g., triacetin, propylene carbonate, ethyl lactate, propylene glycol, oleic acid, dimethylisosorbide, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, glyceryl behenate, glyceryl palmitostearate), surfactants, buffering agents, lubricating agents, humectants, preservatives, colorants and flavorants. Capsules may be hard or soft. Examples of hard capsules include ConiSnap®, DRcaps®, OceanCaps®, Pearlcaps®, Plantcaps®, DUOCAP®, Vcaps®, and Vcaps®. Plus capsules available from Capsugel®. Hard capsules may be prepared, for example, by forming two telescoping capsule halves, filling one of the halves with a fill comprising one or more of the compounds, or pharmaceutically acceptable salts thereof, and sealing the capsule halves together. The fill may be in any suitable form, such as dry powder, granulation, suspension or liquid. Examples of soft capsules include soft gelatin (also called softgel or soft elastic) capsules, such as SGcaps®. Soft capsules may be prepared, for example, by rotary die, plate, reciprocating die or Accogel® machine method. In embodiments, the capsule may be a liquid-filled hard capsule or a soft-gelatin capsule.

[0110] Tablets can be made by compression or molding, optionally with one or more accessory' ingredients. Compressed tablets can be prepared by compressing in a suitable machine, one or more of the compounds or pharmaceutically acceptable salts thereof, in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets can be optionally coated or scored and can be formulated so as to provide sustained, extended, delayed or controlled release. Methods of formulating such sustained, extended, delayed or controlled release compositions are known in the art and disclosed in issued U.S. patents, including but not limited to U.S. Pat. Nos. 4,369, 174 and 4,842,866, and the references cited therein. Coatings, for example enteric coatings, can be used for delivery of compounds to the intestine (see. e.g., U.S. Pat. Nos. 6,638,534; 5,217,720; 6,569,457; and the references cited therein). Tn addition to tablets, other dosage forms, such as capsules, granulations and gel-caps, can be formulated to provide sustained, extended, delayed or controlled release.[OHl] In one embodiment, the pharmaceutical composition is formulated for parenteral administration. Examples of a pharmaceutical composition suitable for parenteral administration include aqueous sterile injection solutions and non-aqueous sterile injection solutions, each containing, for example, anti-oxidants, buffers, bacteriostatic agents and / or solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous sterile suspensions and non-aqueous stenle suspensions, each containing, for example.suspending agents and / or thickening agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampules or vials, and can be stored in a freeze dried (lyophilized) condition requiting only the addition of a sterile liquid carrier, such as water, immediately prior to use. In one embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0112] In some embodiments, the pharmaceutical composition further includes a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient may be any substance, not itself a therapeutic agent, used as a carrier, diluent, adjuvant, binder, and / or vehicle for delivery of a therapeutic agent to a subject, or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a compound or pharmaceutical composition into a unit dosage form for administration. Pharmaceutically acceptable excipients are known in the pharmaceutical arts and are disclosed, for example, in Remington: The Science and Practice of Pharmacy, 21. sup. st Ed. (Lippincott Williams & Wilkins, Baltimore, Md., 2005). As will be known to those in the art, pharmaceutically acceptable excipients can provide a variety' of functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners. Examples of pharmaceutically acceptable excipients include without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, and hydroxypropylcellulose; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0113] Materials used in preparing the pharmaceutical compositions can be non-toxic in the amounts used. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of animal (e.g., human), the particular form of the compounds, or pharmaceutically acceptable salts thereof, the manner ofadministration, the composition employed, and the severity of the disease or condition being treated.

[0114] In addition to administering the compound as a raw chemical, the compounds of the disclosure may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds into preparations which can be used pharmaceutically. The preparations, particularly those preparations which can be administered orally or topically and which can be used for one type of administration, such as tablets, dragees, slow release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by intravenous infusion, injection, topically or orally, contain from about 0.01 to 99 percent, in one embodiment from about 0.25 to 75 percent of active compound(s), together with the excipient.

[0115] The pharmaceutical compositions of the disclosure may be administered to any subject which may experience the beneficial effects of the compounds of the disclosure. Foremost among such subject are mammals, e.g., humans, although the disclosure is not intended to be so limited. Other patients include veterinary animals (cows, sheep, pigs, horses, dogs, cats and the like).

[0116] The compounds and pharmaceutical compositions thereof may be administered by any means that achieve their intended purpose. For example, administration may be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal or topical routes. Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0117] The pharmaceutical preparations of the present disclosure are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.

[0118] Suitable excipients are, in particular, fdlers such as saccharides, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders suchas starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinyl pyrrolidone. If desired, disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate, are used. Dy e stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

[0119] Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds are in one embodiment dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, stabilizers may be added.

[0120] Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of one or more of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

[0121] Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example, water-soluble salts and alkaline solutions. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty’ oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate ortriglycerides or polyethylene gly col-400. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and / or dextran. Optionally, the suspension may also contain stabilizers.

[0122] The topical compositions of this disclosure are formulated in one embodiment as oils, creams, lotions, ointments and the like by choice of appropriate carriers. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than Cl 2). The carriers may be those in which the active compounds are soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Additionally, transdermal penetration enhancers can be employed in these topical formulations. Examples of such enhancers can be found in U.S. Pat. Nos. 3,989,816 and 4,444,762; each herein incorporated by reference in its entirety.

[0123] Ointments may be formulated by mixing a solution of the active ingredient in a vegetable oil such as almond oil with warm soft paraffin and allowing the mixture to cool. A typical example of such an ointment is one which includes about 30% almond oil and about 70% white soft paraffin by weight. Lotions may be conveniently prepared by dissolving the active ingredient, in a suitable high molecular weight alcohol such as propylene glycol or polyethylene glycol.

[0124] In some embodiments of the present disclosure, one or more of the compounds according to Formula (1), (2), and (3), or pharmaceutically acceptable salts thereof, can be employed under a variety of conditions and therapeutic uses to treat a variety of immunological conditions, including cancer.

[0125] The dose to be administered to a subject in need thereof may vary depending upon a variety7of factors including the activity of the particular compositions of the present disclosure employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compositions employed, the age, sex, weight, size, condition, general health, the prior medical history of the patient being treated, target disease, the purpose of the treatment, conditions, the immunogenicity of the entity, and the accessibility of the target cells in the biological matrix and the like. When the combination of the present disclosure is used for treating various conditions and diseases directly or indirectly associated with immune checkpoints, in anadult subject, it may be advantageous to intravenously or subcutaneously administer one or more of the compounds of the present disclosure.

[0126] In vanous embodiments, the appropriate dose of the active compounds described herein is made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment. In some embodiments, sound medical practice ill dictate that the initial dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects. Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced, tissue damage, or estimated activity' or stage in a cancer disease course. In some embodiments, the actual dosage levels of the active compounds in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active compound which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the patient.

[0127] Compositions comprising the combination of the disclosure can be administered to the subject, for example, a human subject by one or more administration modalities, for example, continuous infusion, or by doses at intervals of, e.g., one day, one week, or 1-7 times per week. Doses may be provided parenterally, for example, intravenously, or subcutaneously.

[0128] By way of illustration only, and taking into consideration various factors for determining appropriate doses and dosing frequencies, an example dose of one or more of the compounds, or pharmaceutically acceptable salts thereof, to be administered to a subject in need thereof can include a single dose of one or more of the compounds, or pharmaceutically acceptable salts thereof, about 0.01 to about 100 mg / kg body weight, more preferably about 0.02 to about 7, about 0.03 to about 5, or about 0.05 to about 3 mg / kg body weight dosed, once or more times per day, and / or one or more times per week, for example, for one to four weeks, or one to eight weeks, or one to twelve eeks, or one to fourteen weeks.

[0129] In some embodiments, an example dosing regimen can include administration of a maximal dose or dosing frequency that avoids significant undesirable side effects. In some embodiments, a total weekly dose of each active compound of the combination, independently may be at least 0.05 pg / kg body weight, at least 0.2 pg / kg, at least 0.5 pg / kg, at least 1 pg / kg, at least 10 pg / kg, at least 100 pg / kg, at least 0.2 mg / kg, at least 0.5 mg / kg,at least 1.0 mg / kg, at least 2.0 mg / kg, at least 10 mg / kg, at least 15 mg / kg, at least 20 mg / kg, at least 25 mg / kg, or at least 50 mg / kg, or at least or at least 100 mg / kg. In another example, an illustrative dose of each active compound of the combination of the disclosure, to be administered to a subject in need thereof may be about 0.001 mg / kg to about 200 mg / kg of the subject’s body weight.

[0130] The dosage to a subject in need thereof, may be between 0.001 mg / kg and 200 mg / kg, 0.001 mg / kg and 100 mg / kg, 0.001 mg / kg and 50 mg / kg, 0.001 mg / kg and 25 mg / kg, 0.001 mg / kg and 10 mg / kg, 0.001 mg / kg and 5 mg / kg, 0.001 mg / kg and 1 mg / kg, 0.001 mg / kg and 0.5 mg / kg and any dosage amount there between. As non-limiting examples, treatment according to the present disclosure may be provided as a daily dosage of one or more of the compounds, or pharmaceutically acceptable salts thereof, in an amount of about 0.1-100 mg / kg. such as 0.5. 0.9, 1.0, 1.1. 1.5. 2, 3, 4. 5, 6, 7. 8. 9, 10, 11, 12. 13. 14. 15. 16. 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90, or 100 mg / kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least one of week 1, 2. 3, 4, 5. 6, 7, 8. 9, 10, 11. 12. 13. 14. 15. 16. 17. 18, 19 ,or 20 after initiation of treatment, or any combination thereof, using single or divided doses of every 24, 12, 8, 6, 4, or 2 hours, or any combination thereof.

[0131] Depending on the severity7of the condition, and the various factors discussed herein, the dose, frequency and the duration of the treatment can be adjusted accordingly, in view of proper medical standards known to those of skill in the art. In certain exemplary embodiments, each active agent of the combination of the disclosure can be administered as an initial dose of at least about 0. 1 mg to about 800 mg, about 1 to about 500 mg, about 5 to about 300 mg, or about 10 to about 200 mg, to about 100 mg. or to about 50 mg. The first dose of one or both active agents of the combination may be an initial loading dose, to be followed subsequently by a plurality of maintenance doses. With regard to H027-4038C in particular, the dose may be less than that of DCV, given its improved binding strength.

[0132] In certain example embodiments, the initial dose may be followed by administration of a second or a plurality7of subsequent doses of the antibody or antigen-binding fragment thereof in an amount that can be approximately the same or less than that of the initial dose, wherein the subsequent doses are separated by at least 1 day to 3 days; at least one week, at least 2 weeks; at least 3 weeks; at least 4 weeks; at least 5 weeks; at least 6 weeks; at least 7 weeks; at least 8 weeks; at least 9 weeks; at least 10 weeks; at least 12 weeks; or at least 14 weeks, or doses of the combination of the disclosure may berepeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days. 3 months, or at least 6 months.

[0133] The route of administration of the compositions containing one or more of the compounds, or pharmaceutically acceptable salts thereof, may be independently administered, or administered as a combination in a single formulation by, e.g., topical or cutaneous application, injection or infusion by intravenous, intraperitoneal, subcutaneous, intracerebral, intramuscular, intraocular, intraarterial, intradermal, intracerebrospinal, intralesional, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion, or by sustained release systems or an implant. The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present disclosure.

[0134] Examples include, but certainly are not limited to AUTOPENTM (Owen Mumford. Inc., Woodstock, UK), DIS-ETRONIC™ pen (Disetronic Medical Systems, Burghdorf, Switzerland), HUMALOG MIX 75 / 25TM pen, HUMA-LOG™ pen, HUMALIN 70 / 30TM pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nor-disk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PROTM OPTIPEN STARLETTM, and OPTICLIKTM (Sanofi-Aventis, Frankfurt, Germany), as example pen-based delivery methods contemplated herein in the administration of the present compositions. Illustrative examples of pen based devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, the SOLOSTAR™ pen (Sanofi-Aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (Eh Lilly).

[0135] Generally, the oral dosage of one or more of the compounds, or pharmaceutically acceptable salts, administered to an animal, for example a human subject, is about 0.001 mg / kg to about 100 mg / kg of the animal's body weight, more ty pically about 0.1 mg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg. 25 mg / kg, 50 mg / kg. 100 mg / kg, 150 mg / kg, 200 mg / kg, 250 mg / kg, or 300 mg / kg to about 500 mg / kg of the subject’s body weight. In some aspects, the dosage of one or more of the compounds, or pharmaceutically acceptable salts, administered to the subject is about 1 mg, about 5 mg, or about 10 mg to about 350 mg per day. or from about 1 mg, about 5 mg, about 10 mg, about 15 mg or about 20 mg to about 100 mg per day.

[0136] One or more of the compounds, or pharmaceutically acceptable salts thereof, can be administered on a daily, weekly, biweekly or monthly schedule, according to the desired effect. In some aspects one or more of the compounds, or pharmaceutically acceptable salts thereof, can be administered from about 1 to 5, about 1 to about 10, about 1 to about 15, or more cycles, wherein each cycle is a month in duration. The doses within each cycle can be given on daily (including once daily, twice daily, or more than twice daily), every other day, twice weekly, weekly, bi-weekly, once every three weeks or monthly basis. A cycle may optionally include a resting period. Alternatively, a resting period can be included between cycles. In some aspects, administration will be for the duration of the disease.

[0137] As described herein, the amount of one or more of the compounds, or pharmaceutically acceptable salts thereof, that is effective in the methods described herein will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.

[0138] Compositions within the scope of this disclosure include all compositions wherein one or more of the compounds, or pharmaceutically acceptable salts thereof, are contained in an amount which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art. Typically, one or more of the compounds, or pharmaceutically acceptable salts thereof, may be administered to mammals, e.g. humans, orally at a dose of 0.0025 to 100 mg / kg, or an equivalent amount of the pharmaceutically acceptable salt thereof, per day of the body weight of the mammal being treated for the cancer being treated. In one embodiment, about 0.01 to about 25 mg / kg is orally administered to treat, ameliorate, or prevent such disorders. For intravenous injection or infusion injection, the dose of the checkpoint inhibitor antibody or antigen binding fragment thereof would be about 0. 1 to about 1000 mg / kg, or from about 0.1 mg / kg to about 500 mg / kg patient weight.

[0139] The unit oral dose of one or more of the compounds, or pharmaceutically acceptable salts thereof, may comprise from about 0.01 mg to about 1000 mg, for example, about 0.1 to about 100 mg of the compound(s). The unit dose may be administered one ormore times daily as one or more tablets or capsules each containing from about 0. 1 to about 10 mg, conveniently about 0.25 to 50 mg of the compound(s).

[0140] In a topical formulation, one or more of the compounds, or pharmaceutically acceptable salts thereof, may be present at a concentration of about 0.01 to 100 mg per gram of carrier. In a one embodiment, the compound(s) are present at a concentration of about 0.07-1.0 mg / mL, for example, about 0.1-0.5 mg / mL, and in one embodiment, about 0.4 mg / mL.

[0141] The present disclosure may be used to treat a neoplastic disease, such as solid or non-solid cancers. As used herein, "treatment" encompasses the prevention, reduction, control and / or inhibition of a neoplastic disease. Such diseases include those that result in TRIB2-positive cancer cells, including ERPC cells and TRIB2-positive lung cancer cells, and including but not limited to: non-small cell lung cancer, small cell lung cancer, oat cell cancer, triple negative breast cancer, sarcomatoid kidney cancer, melanoma, pancreatic neuroendocrine cancer, adenocarcinoma, squamous cell carcinoma, large cell (undifferentiated) carcinoma, papillary carcinoma, adenosquamous carcinoma, carcinoid tumors, adenoid cystic carcinomas lymphomas, andsarcomas. and sarcomatoid carcinoma. In various embodiments, the lung cancers described in the foregoing are TRIB2-positive lung cancers. The present disclosure provides an effective method for treating TRIB2- positive cancer, such as prostate cancer, in particular, ERPC, and / or lung cancer by administering a therapeutically effective amount of one or more of the compounds to a subject in need thereof. The disease may include neoplasia, tumors, and cancers include benign, malignant, metastatic and non-metastatic types, and include any stage (I, II, III, IV or V) or grade (Gl, G2, G3, etc.) of neoplasia, tumor, or cancer, or a neoplasia, tumor, cancer or metastasis that is progressing, worsening, stabilized or in remission. The tumor may be metastatic or a malignant tumor. The present disclosure provides an effective method for treating TRIB2-positive cancers by administering a therapeutically effective amount of one or more of the compounds to a subject in need thereof.

[0142] Some embodiments of the present disclosure provide methods for administering an effective amount of a compound in accordance with Formulas (1), (2), and / or (3), and at least one additional therapeutic agent (including, but not limited to, chemotherapeutic antineoplastics, apoptosis-modulating agents, antimicrobials, antivirals, antifungals, and anti-inflammatory' agents) and / or therapeutic technique (e.g., surgical intervention, and / or radiotherapies). In a particular embodiment, the additional therapeutic agent(s) is an anticancer agent.

[0143] A number of suitable anticancer agents are contemplated for use in the methods of the present disclosure. Indeed, the present disclosure contemplates, but is not limited to, administration of numerous anticancer agents such as: agents that induce apoptosis; polynucleotides (e.g., anti-sense, ribozymes, siRNA); polypeptides (e.g., enzy mes and antibodies); biological mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones; platinum compounds; monoclonal or polyclonal antibodies (e.g., antibodies conjugated with anticancer drugs, toxins, defensins); toxins; radionuclides; biological response modifiers (e.g., interferons (e.g., IFN-a) and interleukins (e.g., IL-2)); adoptive immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell differentiation (e.g.. all-trans-retinoic acid); gene therapy reagents (e.g.. antisense therapy reagents and nucleotides); tumor vaccines; angiogenesis inhibitors; proteosome inhibitors: NF-KB modulators; anti-CDK compounds; HDAC inhibitors; and the like. Numerous other examples of chemotherapeutic compounds and anticancer therapies suitable for co- administration with the disclosed compounds are known to those skilled in the art.

[0144] In certain embodiments, anticancer agents comprise agents that induce or stimulate apoptosis. Agents that induce apoptosis include, but are not limited to. radiation (e.g.. X-rays, gamma rays, UV); tumor necrosis factor (TNF)-related factors (e.g., TNF family receptor proteins, TNF family ligands, TRAIL, antibodies to TRAIL-RI or TRAIL- R2); kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitor, vascular growth factor receptor (VGFR) kinase inhibitor, fibroblast growth factor receptor (FGFR) kinase inhibitor, platelet-derived growth factor receptor (PDGFR) kinase inhibitor, and Bcr- Abl kinase inhibitors (such as GLEEVEC)); antisense molecules; antibodies (e.g., HERCEPTIN, RITUXAN, ZEVALIN, and AVASTIN); anti-estrogens (e.g., raloxifene and tamoxifen); anti-androgens (e.g.. flutamide, bicalutamide. finasteride, aminoglutethamide, ketoconazole, and corticosteroids); cyclooxygenase 2 (COX-2) inhibitors (e.g., celecoxib. meloxicam, NS-398, and non-steroidal anti-inflammatory drugs (NSAIDs)); anti-inflammatory drugs (e.g., butazolidin, DECADRON, DELTASONE, dexamethasone, dexamethasone intensol, DEXONE, HEXADROL, hydroxychloroquine, METICORTEN, ORADEXON, ORASONE, oxyphenbutazone, PEDIAPRED, phenylbutazone, PLAQUENIL, prednisolone, prednisone, PRELONE, and TANDEARIL); and cancer chemotherapeutic drugs (e.g., irinotecan (CAMPTOSAR), CPT-11, fludarabine (FLUDARA), dacarbazine (DTIC), dexamethasone, mitoxantrone, MYLOTARG, VP- 16, cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin, gemcitabine, bortezomib, gefitinib,bevacizumab, TAXOTERE or TAXOL); cellular signaling molecules; ceramides and cytokines; staurosporine, and the like.

[0145] In still other embodiments, the compositions and methods of the present disclosure include a compound of Formulas (1), (2), and / or (3), and at least one anti- hyperproliferative or antineoplastic agent selected from alkylating agents, antimetabolites, and natural products (e.g., herbs and other plant and / or animal derived compounds).

[0146] Alkylating agents suitable for use in the present compositions and methods include, but are not limited to: 1) nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-sarcolysin); and chlorambucil); 2) ethylenimines and methylmelamines (e.g., hexamethylmelamine and thiotepa); 3) alky l sulfonates (e.g., busulfan); 4) nitrosoureas (e.g., carmustine (BCNU); lomustine (CCNU); semustine (methyl-CCNU); and streptozocin (streptozotocin)); and 5) triazenes (e.g.. dacarbazine (DTIC; dimethyltriazenoimid-azolecarboxamide).

[0147] In some embodiments, antimetabolites suitable for use in the present compositions and methods include, but are not limited to: 1) folic acid analogs (e g., methotrexate (amethopterin)); 2) pyrimidine analogs (e.g., fluorouracil (5 -fluorouracil; 5- FU), floxuridine (fluorode-oxyuridine; FudR), and cytarabine (cytosine arabinoside)); and 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine; 6-MP), thioguanine (6- thioguanine; TG), and pentostatin (2'-deoxycoformycin)).

[0148] In still further embodiments, chemotherapeutic agents suitable for use in the compositions and methods of the present disclosure include, but are not limited to: 1) vinca alkaloids (e.g., vinblastine (VLB), vincristine); 2) epipodophyllotoxins (e.g., etoposide and teniposide); 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin; rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin). and mitomycin (mitomycin C)); 4) enzymes (e.g., L-asparaginase); 5) biological response modifiers (e.g., interferon-alfa); 6) platinum coordinating complexes (e.g., cisplatin (cis-DDP) and carboplatin); 7) anthracenediones (e.g., mitoxantrone); 8) substituted ureas (e.g., hydroxyurea); 9) methylhydrazine derivatives (e.g., procarbazine (N-methylhydrazine; MIH)); 10) adrenocortical suppressants (e.g.. mitotane (o,p'-DDD) and aminoglutethimide); 11) adrenocorticosteroids (e.g., prednisone); 12) progestins (e.g., hydroxy progesterone caproate, medroxyprogesterone acetate, and megestrol acetate); 13) estrogens (e.g., diethylstilbestrol and ethinyl estradiol); 14) antiestrogens (e.g., tamoxifen); 15) androgens (e.g.. testosterone propionate and fluoxymesterone); 16) antiandrogens (e g., flutamide): and 17) gonadotropin-releasing hormone analogs (e.g., leuprolide).

[0149] Any oncolytic agent that is routinely used in a cancer therapy context may be used in the compositions and methods of the present disclosure, to the extent it is operationally feasible. For example, the U.S. Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States. International counterpart agencies to the U.S.F.D.A. maintain similar formularies. Those skilled in the art will appreciate that the "product labels" required on all U.S. approved chemotherapeutics describe approved indications, dosing information, toxicity data, and the like, for example agents.

[0150] Anticancer agents further include compounds which have been identified to have anticancer activity. Examples include, but are not limited to, 3-AP, 12-0- tetradecanoylphorbol- 13 -acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI-PEG 20. AE-941. AG-013736. AGRO 1OO. alanosine. AMG 706. antibody G250, antineoplastons, AP23573, apaziquone, APC8015, atiprimod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BGOOOO 1, bicalutamide, BMS 247550, bortezomib, bryostatin-1, buserelin, calcitriol, CCI-779, CDB-2914, cefixime, cetuximab, CG0070, cilengitide, clofarabine, combretastatin A4 phosphate, CP-675,206, CP-724, 714, CpG 7909, curcumin, decitabine, DENSPM, doxercalciferol, E7070, E7389, ecteinascidin 743, efaproxiral, eflomithine, EKB-569, enzastaurin, erlotinib, exisulind, fenretinide, flavopiridol, fludarabine, flutamide, fotemustine, FR901228, G17DT. galiximab, gefitinib, genistein, glufosfamide, GTI-2040, histrelin, HKI-272, homoharringtonine, HSPPC-96, hul4.18-interleukin-2 fusion protein, HuMax-CD4, iloprost, imiquimod, infliximab, interleukin- 12, IPI-504, irofulven, ixabepilone, lapatinib, lenalidomide, lestaurtinib, leuprolide, LMB-9 immunotoxin, lonafamib, luniliximab, mafosfamide, MB07133, MDX-010, MLN2704, monoclonal antibody 3F8, monoclonal antibody J591, motexafin. MS-275, MVA-MUC1-IL2, nilutamide, nitrocamptothecin, nolatrexed dihydrochloride, nolvadex, NS-9, 06-benzylguanine, oblimersen sodium, ONYX-015, oregovomab, OSI-774, panitumumab, paraplatin, PD-0325901, pemetrexed, PHY906, pioglitazone, pirfenidone, pixantrone, PS-341, PSC 833, PXD 1 0 1, pyrazoloacridine, R1 15777, RADOO 1. ranpimase. rebeccamycin analogue, rhuAngiostatin protein, rhuMab 2C4, rosiglitazone, rubitecan, S-l, S-8184, satraplatin, SB-15992, SGN- 0010, SGN-40, sorafenib, SR3 1 747 A, ST1571, SU011248, suberoylanilide hydroxamic acid, suramin, talabostat, talampanel, tariquidar, temsirolimus, TGFa-PE38 immunotoxin, thalidomide, thymalfasin, tipifamib, tirapazamine, TLK286, trabectedin, trimetrexateglucuronate, TroVax, UCN-1, valproic acid, vinflunine, VNP40101M, volociximab, vorinostat, VX-680. ZD1839. ZD6474. zileuton, and zosuquidar trihydrochloride.

[0151] For a more detailed description of anticancer agents and other therapeutic agents, those skilled in the art are referred to any number of instructive manuals including, but not limited to, the Physician's Desk Reference and to Goodman and Gilman's "Pharmaceutical Basis of Therapeutics" tenth edition, Eds. Hardman et al., 2002.

[0152] The present disclosure provides methods for administering one or more of the compounds with radiation therapy. The invention is not limited by the types, amounts, or deliver}7and administration systems used to deliver the therapeutic dose of radiation to an animal. For example, the animal may receive photon radiotherapy, particle beam radiation therapy, other types of radiotherapies, and combinations thereof. In some embodiments, the radiation is delivered to the animal using a linear accelerator. In still other embodiments, the radiation is delivered using a gamma knife.

[0153] The source of radiation can be external or internal to the subject. External radiation therapy is most common and involves directing a beam of high-energy radiation to a tumor site through the skin using, for instance, a linear accelerator. While the beam of radiation is localized to the tumor site, it is nearly impossible to avoid exposure of normal, healthy tissue. However, external radiation is usually well tolerated by animals. Internal radiation therapy involves implanting a radiation-emitting source, such as beads, wires, pellets, capsules, particles, and the like, inside the body at or near the tumor site including the use of delivery systems that specifically target cancer cells (e.g., using particles attached to cancer cell binding ligands). Such implants can be removed following treatment, or left in the body inactive. Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial irradiation, intracavity irradiation, radioimmunotherapy, and the like.

[0154] The subject may optionally receive radiosensitizers (e g., metronidazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (ludR), nitroimidazole, 5- substituted-4-nitroimidazoles, 2H-isoindol ediones, [[(2-bromoethyl )-amino] methyl] - nitro-lH-imidazole- 1 -ethanol, nitroaniline derivatives, DNA-affinic hypoxia selective cytotoxins, halogenated DNA ligand, 1,2,4 benzotriazine oxides, 2-nitroimidazole derivatives, fluorine-containing nitroazole derivatives, benzamide, nicotinamide, acridine- intercalator, 5- thiotretrazole derivative, 3-nitro-l,2,4-triazole, 4,5-dinitroimidazole derivative, hydroxylated texaphrins, cisplatin, mitomycin, tiripazamine, nitrosourea, mercaptopurine, methotrexate, fluorouracil, bleomycin, vincristine, carboplatin, epirubicin,doxorubicin, cyclophosphamide, vindesine, etoposide, paclitaxel, heat (hyperthermia), and the like), radioprotectors (e.g., cysteamine, aminoalkyl dihydrogen phosphorothioates, amifostine (WR 2721). IL-1. IL-6, and the like). Radiosensitizers enhance the killing of tumor cells. Radioprotectors protect healthy tissue from the harmful effects of radiation.

[0155] Any t pe of radiation can be administered to a subject, so long as the dose of radiation is tolerated by the subject without unacceptable negative side-effects. Suitable types of radiotherapy include, for example, ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) or particle beam radiation therapy (e.g., high linear energy radiation). Ionizing radiation is defined as radiation comprising particles or photons that have sufficient energy to produce ionization, i.e., gain or loss of electrons (as described in, for example, U.S. 5,770,581 incorporated herein by reference in its entirety)- The effects of radiation can be at least partially controlled by the clinician. In one embodiment, the dose of radiation is fractionated for maximal target cell exposure and reduced toxicity.

[0156] In one embodiment, the total dose of radiation administered to a subject is about .01 Gray (Gy) to about 100 Gy. In another embodiment, about 10 Gy to about 65 Gy ( e.g.. about 15 Gy. 20 Gy. 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, or 60 Gy) are administered over the course of treatment. While in some embodiments a complete dose of radiation can be administered over the course of one day, the total dose is ideally fractionated and administered over several days. Desirably, radiotherapy is administered over the course of at least about 3 days, e.g., at least 5. 7, 10, 14, 17. 21. 25, 28, 32, 35, 38, 42, 46, 52, or 56 days (about 1-8 weeks). Accordingly, a daily dose of radiation will comprise approximately 1-5 Gy (e.g., about 1 Gy, 1.5 Gy, 1.8 Gy, 2 Gy, 2.5 Gy, 2.8 Gy, 3 Gy, 3.2 Gy, 3.5 Gy, 3.8 Gy, 4 Gy, 4.2 Gy, or 4.5 Gy), or 1-2 Gy (e.g., 1.5-2 Gy). The daily dose of radiation should be sufficient to induce destruction of the targeted cells. If stretched over a period, in one embodiment, radiation is not administered even- day, thereby allowing the subject to rest and the effects of the therapy to be realized. For example, radiation desirably is administered on 5 consecutive days, and not administered on 2 days, for each week of treatment, thereby allowing 2 days of rest per week. However, radiation can be administered 1 day / week. 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or all 7 days / week, depending on the subject’s responsiveness and any potential side effects.

[0157] Radiation therapy can be initiated at any time in the therapeutic period. In one embodiment, radiation is initiated in week 1 or week 2, and is administered for the remaining duration of the therapeutic period. For example, radiation is administered inweeks 1-6 or in weeks 2-6 of a therapeutic period comprising 6 weeks for treating, for instance, a solid tumor. Alternatively, radiation is administered in weeks 1-5 or eeks 2-5 of a therapeutic period comprising 5 weeks. These example radiotherapy administration schedules are not intended, however, to limit the present disclosure.

[0158] Antimicrobial therapeutic agents may also be used as therapeutic agents in the present disclosure. Any agent that can kill, inhibit, or otherwise attenuate the function of microbial organisms may be used, as well as any agent contemplated to have such activities. Antimicrobial agents include, but are not limited to, natural and synthetic antibiotics, antibodies, inhibitory proteins (e.g., defensins), antisense nucleic acids, membrane disruptive agents and the like, used alone or in combination. Indeed, any ty pe of antibiotic may be used including, but not limited to, antibacterial agents, antiviral agents, antifungal agents, and the like.

[0159] In some embodiments, one or more compounds of the present disclosure and one or more therapeutic agents or anticancer agents are administered to a subject under one or more of the following conditions: at different periodicities, at different durations, at different concentrations, by different administration routes, etc. In some embodiments, one or more of the compounds are administered prior to the therapeutic or anticancer agent, e.g., 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours; 1, 2, 3, 4, 5, or 6 days; or 1, 2, 3, or 4 weeks prior to the administration of the therapeutic or anticancer agent. In some embodiments, the compound is administered after the therapeutic or anticancer agent, e.g., 0.5, 1, 2. 3, 4, 5. 10, 12, or 18 hours; 1, 2, 3, 4, 5, or 6 days; or 1, 2, 3, or 4 weeks after the administration of the anticancer agent. In some embodiments, one or more of the compounds and the therapeutic or anticancer agent are administered concurrently but on different schedules, e.g., the compound is administered daily while the therapeutic or anticancer agent is administered once a week, once every two weeks, once every three weeks, or once every four w eeks. In other embodiments, one or more of the compounds are administered once a yveek while the therapeutic or anticancer agent is administered daily, once a yveek, once every tw o weeks, once every three weeks, or once every four yveeks.

Claims

CLAIMS1. A composition for treating cancer, comprising a therapeutically effective amount of a compound selected from Formula (1), Formula (2), or a combination of Formula (1) and Formula (2):or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein:R isXI isX2 iswherein B is a terphenyl group.

2. The composition of claim 1. wherein the terphenyl group is an ortho-terphenyl group.

3. The composition of claim 1 or 2, wherein the compound comprises a therapeutically effective amount of Formula (1), and Formula (1) is:

4. The composition of any one of claims 1 to 3. wherein the compound comprises a therapeutically effective amount of Formula (2), and Formula (2) is:

5. The composition of any one of claims 1 to 3, wherein the compound comprises a therapeutically effective amount of Formula (2), and Formula (2) is:

6. The composition of any one of claims 1 to 5. wherein the cancer is an enzalutamide- resistant cancer.

7. The composition of any one of claims 1 to 6, wherein the cancer is castration resistant prostate cancer (CRPC), small cell lung cancer (SCLC), pancreatic neuroendocrine cancer (PNEC), triple negative breast cancer (TNBC), sarcomatoid kidney cancer, or melanoma.

8. A method of treating cancer, comprising administering the composition of any one of claims 1 to 5 to a subject in need thereof.

9. The method of claim 8, wherein the composition inhibits Tribbles homolog 2 (TRIB2) pseudokinase.

10. The method of claim 8 or 9, wherein the compound of the composition is configured to bind with Ser-133 and Val-92 of TRIB2.

11. The method of any one of claims 8 to 10, wherein the compound of the composition is configured to hydrogen bond with Ser-133 and Val-92 of TRIB2.

12. The method of any one of claims 8 to 11, further comprising the step of administering one or more of Enzalutamide, Apalutamide, Darolutamide, and abiraterone in a therapeutically effective amount.

13. A composition for treating cancer, comprising a therapeutically effective amount of:or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein A is a non-oxygenated pyrrolidinyl imidazole or a pyrrolidinyl imidazole having three or fewer nitrogen atoms.

14. The composition of claim 13, wherein A is 2-(2-pyrrolidinyl)-lH-imidazole.

15. The composition of claim 13 or 14, wherein the cancer is an enzalutamide-resistant cancer.

16. The composition of any one of claims 13 to 15, wherein the cancer is castration resistant prostate cancer (CRPC), small cell lung cancer (SCLC), pancreatic neuroendocrine cancer (PNEC), triple negative breast cancer (TNBC), sarcomatoid kidney cancer, or melanoma.

17. A method of treating cancer, comprising administering the composition of claim 13 or 14 to a subject in need thereof.

18. The method of claim 17, wherein the composition inhibits Tribbles homolog 2 (TRIB2) pseudokinase.

19. The method of claim 17 or 18, wherein the compound of the composition is configured to bind with Ser- 133 and Val-92 of TR1B2.

20. The method of any one of claims 17 to 19, wherein the compound of the composition is configured to hydrogen bond with Ser- 133 and Val-92 of TRIB2.

21. The method of any one of claims 17 to 20, further comprising the step of administering one or more of Enzalutamide, Apalutamide, Darolutamide, and abiraterone in a therapeutically effective amount.

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