Methods and compositions for inhibiting c-myc

Abstract

Compositions and methods for treating, inhibiting, preventing or reducing disorders and diseases in a subject by administering one or more anti-c-MYC agents are disclosed. In one aspect, a subject having a c-Myc-mediated disease, disorder or condition is treated with a compound of the disclosure including a compound selected from Formula (I), (I) wherein R is H, an in vivo cleavable linker or group, or a leaving group in aqueous solution and R1 and R2 are independently, H, alkyl, an aryl, a substituted alkyl, a substituted phenyl, a substituted aryl, or a combination thereof.

Description

Attorney Docket No. 1194MS-540WO1METHODS AND COMPOSITIONS FOR INHIBITING C-MYCCROSS REFERENCE OF RELATED APPLICATION

[0001] This application claims the benefit of United States provisional patent application No. 63 / 702,860 filed October 3, 2024, the disclosure of which is incorporated herein by reference.FIELD OF THE DISCLOSURE

[0002] This disclosure relates to compositions and methods for treating, inhibiting, preventing or reducing disorders and diseases in a subject by administering one or more anti-c- MYC agents of the present disclosure.BACKGROUND

[0003] The oncoprotein c-MYC is a pleiotropic transcription factor that modulates global gene expression and regulates critical cellular processes including proliferation, differentiation, cell cycle, metabolism and apoptosis. Strong evidence supports aberrant c-MYC expression as a driver of both tumor initiation and maintenance and is associated with various diseases and disorders including cancers. The MYC oncogene family includes c-MYC, MYCN (N-MYC) and MYCL (L-MYC). c-MYC is ubiquitously expressed during tissue development and in a broad variety of tumors.

[0004] c-MYC is estimated to be aberrantly expressed in up to 70% of human cancers, many of which are highly aggressive (e.g. acute leukemia and high-grade lymphoma) and / or show poor response to treatment (e.g., small-cell lung carcinoma and neuroblastoma).

[0005] Several approaches have attempted to inhibit c-MYC directly or indirectly at all levels of its regulation. However, despite massive efforts, targeting c-MYC with clinical grade small molecules still represents an intractable challenge.

[0006] Accordingly, there is a long-felt and unmet need for new compositions and methods to treat, inhibit, prevent or reduce disorders and diseases in a subject by administeringAttorney Docket No. 1194MS-540WO1 one or more anti-c-MYC agents as well as to improve the performance, outcomes, and tolerability of existing therapeutic agents.SUMMARY OF THE INVENTION

[0007] In one aspect, the present disclosure includes a method of treating a subject having a c-Myc-mediated disease, disorder or condition comprising: obtaining a baseline biological sample from the subject and measuring a baseline level of c-Myc or c-Myc activity in the baseline biological sample; then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of c-Myc or c-Myc activity in the post-treatment biological sample, and further comprising administering the compound to the subject if the post-treatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity. In one aspect, one or more such steps are combined with any of the other methods disclosed herein.

[0008] In one aspect, the present disclosure includes a method for identifying a candidate suitable for treatment with a c-Myc-inhibitor compound comprising: obtaining a baseline biological sample from the subject and measuring a baseline level of c-Myc or c-Myc activity in the baseline biological sample; then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of c-Myc or c-Myc activity in the post-treatment biological sample, and identifying the subject as a suitable candidate for treating with the c-Myc-inhibitor compound if the post-treatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity. In one aspect, one or more such steps are combined with any of the other methods disclosed herein.Attorney Docket No. 1194MS-540WO1

[0009] In one aspect, the present disclosure includes obtaining a baseline biological sample from the subject and measuring a baseline level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity in the baseline biological sample; then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF- KB activity in the post-treatment biological sample, and identifying the subject as a suitable candidate for treating with the c-Myc-inhibitor compound if the post-treatment level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity is lower than the baseline level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB. In one aspect, one or more such steps are combined with any of the other methods disclosed herein.

[0010] In one aspect, the present disclosure includes obtaining a baseline biological sample from the subject and measuring a baseline level of ROS, pAMPK, pACC, pRaptor, or p53 in the baseline biological sample; then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of ROS, pAMPK, pACC, pRaptor, or p53 in the post-treatment biological sample, and identifying the subject as a suitable candidate for treating with the c-Myc- inhibitor compound if the post-treatment level of ROS, pAMPK, pACC, pRaptor, or p53 is higher than the baseline level of ROS, pAMPK, pACC, pRaptor, or p53. In one aspect, one or more such steps are combined with any of the other methods disclosed herein.

[0011] In any of the aspects disclosed herein, the baseline biological sample and the posttreatment biological sample may each be a tumor tissue sample.BRIEF DESCRIPTION OF THE DRAWINGSAttorney Docket No. 1194MS-540WO1

[0012] FIG. 1 is a bar graph showing the % relative activity of recombinant human c- MYC after 30 minute incubation with increasing concentrations of misetionamide. U = untreated control.

[0013] FIGs. 2A and 2B are bar graphs showing the % relative activity of c-MYC in cell lysates from Pane Tul (FIG. 2A) and Bo80 (FIG. 2B) cells after 24 hour incubation with increasing concentrations of misetionamide. C = untreated control.

[0014] FIGs. 3A-3B and 4A-4B show relative amounts of c-MYC in cell lysates from Pane Tul (FIG. 3A-3B) and Bo80 (FIG. 4A-4B) cells after incubation with increasing concentrations of misetionamide for 6 hours, 12 hours, and 24 hours. N = not treated.

[0015] FIG. 5 graphically presents the effects on generation of ROS (panels A and B), inhibition of NF-KB in Pane Tul (panel C) and BxPC3 (panel D) cells, and inhibition of NF-KB in nuclear lysates from Pane Tul (panel E) and BxPC3 (panel F) cells by administration of GP- 2250. C, non-treated control; NAC, n-acetylcysteine; NC, negative control; NF-KB, nuclear factor kappa-light-chain-enhancer of activated B cells; ROS, reactive oxygen species; SD, standard deviation; UC, untreated control. *p < 0.05, significant; **p < 0.01, highly significant; ***p < 0.001, extremely significant.

[0016] FIG. 6 (panel A) shows is a western blot of phosphorylated AMPK (pAMPK) and cyclin DI from Pane Tul and BxPC3 cells treated with GP-2250 at various concentrations and times, and (panel B) shows bar graphs showing the quantified amount of pAMPK and cyclin DI relative to negative control. [3-Actin / HSP-9O were used as internal controls. NC, negative control.

[0017] FIG. 7 (panel A) is a western blot of mTOR, phosphorylated ACC (pACC), phosphorylated Raptor (pRaptor), Akt, p53, and Bcl2 from Pane Tul and BxPC3 cells treated with 250 pM and 500 pM GP-2250, respectively, for 6 hours, 12 hours, or 24 hours, and (panel B) shows bar graphs showing the quantified amount of mTOR, pACC, pRaptor, Akt, p53, and Bcl2 relative to the 6 hour treatment group. [3-Actin / HSP-9O were used as internal controls.Attorney Docket No. 1194MS-540WO1

[0018] FIG. 8 expression of cyclin D2 is downregulated following incubation of pancreatic cancer cells PancTul with various concentrations of GP-2250 (250 uM, 500 uM, 1000 uM) for different times (6h, 12h, 24h) as demonstrated by the quantification (upper graph) of Western blots (bottom graph) performed with nuclear extracts. N, control (Vinculin).DETAILED DESCRIPTION

[0019] While aspects of the subject matter of the present disclosure may be embodied in a variety of forms, the following description are merely intended to disclose some of these forms as specific examples of the subject matter encompassed by the present disclosure. Accordingly, the subject matter of this disclosure is not intended to be limited to the forms or aspects so described and illustrated.

[0020] To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific aspects of the invention, but their usage does not delimit the invention, except as outlined in the claims.

[0021] The terms “inhibiting,” “reducing,” or “prevention,” or any variation of these terms, when used in the claims and / or the specification includes any measurable decrease or complete inhibition to achieve a desired result.

[0022] Anti-c-Myc agents of the present disclosure may be administered to any subject in need of inhibiting of c-Myc activity. Such subjects may be at risk of suffering from or suffering from a variety of diseases, disorders and conditions. For example, such diseases, disorders and conditions may be characterized by impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy. AsAttorney Docket No. 1194MS-540WO1 used herein, the phrase “c-MYC-mediated disorder, disease or condition” encompasses any one or more disorder, disease or condition in a subject in need of inhibiting of c-MYC activity including but not limited to diseases, disorders and conditions which may be characterized by impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy, and including, but not limited to any one or more disorder, disease or condition discussed herein.

[0023] The present disclosure provides methods and compositions to inhibit c-MYC targeting cells with aerobic glycolysis. In this type of metabolism, only a small fraction of the glucose flux is used for energy production and can be decreased by c-MYC inhibition. Aerobic glycolysis is found in nearly all types of tumor cells, but not in normal cells. Accordingly, the present disclosure provides methods and compositions having broad spectrum anti-c-MYC activity without general toxicity to normal cells. Further, the present disclosure provides methods and compositions for regulating cells operating with an aerobic glycolytic energy metabolism, e.g., activated endothelial cells and activated immune cells.

[0024] In some aspects, the present disclosure provides methods and compositions to irreversibly inhibit c-MYC. As such, the present disclosure provides a surprising and unexpected advantage over existing therapies, e.g., antibodies, which require continuous dosing and are minimally effective. The present disclosure provides a way to permanently inactivate c- MYC by irreversibly binding to its active site.

[0025] In some aspects, the present disclosure provides methods and compositions to regulate mitochondrial function and protein production to reduce, inhibit, prevent and / or eliminate cancer stem cells (CSCs). In some aspects, the present disclosure provides methods and compositions to increase reactive species, e.g., reactive oxygen species, in tumors and cancerous cells, thereby reducing cancer cell viability without affecting normal cells. In someAttorney Docket No. 1194MS-540WO1 aspects, the present disclosure provides methods and compositions to induce reversion of desmoplastic tissue surrounding cancer cells / tumors to normal extracellular matrix. In some aspects, the present disclosure provides methods and compositions to reduce, inhibit, prevent and / or ablate cytokines. In some aspects, the present disclosure provides methods and compositions for administration to subjects having therapies / conditions that give rise to cytokine release or increased levels of cytokines. In some aspects, the present disclosure provides methods and compositions for reducing, inhibiting, preventing and / or ablating cytokines without interfering with targeted cancer cell cytotoxicity in immune therapies including but not limited to T-cell engaging therapies, e.g., CAR-T and bispecific therapies.

[0026] In some aspects, the present disclosure also provides methods and compositions for treating, reducing, inhibiting, or preventing Achalasia, Addison’s disease, Adult Still's disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti- GBM / Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalomyelitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticarial, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, Benign mucosal pemphigoid, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS), Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome (limited scleroderma), Crohn’s disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressier’s syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’sAttorney Docket No. 1194MS-540WO1 syndrome, graft versus host disease (GVHD), Granulomatosis with Polyangiitis, Graves’ disease,Guillain-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis, pemphigoid gestationis (PG), Hidradenitis Suppurativa (HS) (Acne Inversa), Hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere’s disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis, Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud’s phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome (SPS), Subacute bacterial endocarditis (SBE), Susac’s syndrome, Sympathetic ophthalmia (SO), Takayasu’s arteritis, Temporal arteritis / Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transverse myelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD),Attorney Docket No. 1194MS-540WO1Uveitis, Vasculitis, Vitiligo, Vogt-Koyanagi-Harada Disease, tumors, cancers including, but not limited to carcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, a metastatic solid tumor, and mixed-type cancers, skin diseases (including, but are not limited to, psoriasis, telangiectasia, wound granularization, scleroderma, neovascularization as a consequence of infection (e.g., cat scratch disease, bacterial ulceration, etc.)), macular degeneration or age- related blindness, diabetic ulcers, chronic ulcers and wounds, stroke, traumatic brain injury, neovascularization of the retina, neovascularization of the cornea (such as that caused by trachoma, infections, inflammation, transplantations or trauma), diabetic retinopathy, diabetic retinal edema, diabetic macula edema, ischemic retinopathy, hypertensive retinopathy, occlusive retinopathy, retinopathy of prematurity, neovascularization subsequent to trauma, neovascularization subsequent to infection, neovascularization subsequent to transplantation, neovascularization subsequent to retinal detachment or retinal degeneration, neovascular glaucoma, anterior chamber and / or anterior chamber angle neovascularization, choroidal neovascularization (CNV), subretinal neovascularization, retrolental fibroplasias, ocular histoplasmosis syndrome, myopic degeneration, angioid streaks, uveitis, rubeosis, retrolental fibroplasias, ocular histoplasmosis, and idiopathic central serous chorioretinopathy, amyotrophic lateral sclerosis, sarcoidosis, scleroderma, lupus, Parkinson’s disease, sclerosis, Stevens-Johnson syndrome, neoplasia, Von Willebrand disease, vasculitis, and Kawasaki disease.

[0027] The present disclosure also provides methods and compositions for treating subjects suffering from cardiovascular diseases including but not limited to atherosclerosis, restenosis, atheroma, and haemangioma. Atherosclerosis is a form of chronic vascular injury in which some of the normal vascular smooth cells (VSMC) in the artery wall change their nature and develop dense networks of capillaries in atherosclerotic plaques. These fragile microvessels can cause hemorrhages, leading to blood clotting, with a subsequent decreased blood flow to the heart muscle and heart attack. Restenosis typically occurs after coronary artery bypass surgery, endarterectomy, and heart transplantation, and particularly after heart balloon angioplasty,Attorney Docket No. 1194MS-540WO1 atherectomy, laser ablation or endovascular stenting.

[0028] As used herein, the terms “substantially” and “substantial” refer to a considerable degree or extent. When used in conjunction with, for example, an event, circumstance, characteristic, or property, the terms can refer to instances in which the event, circumstance, characteristic, or property occurs precisely as well as instances in which the event, circumstance, characteristic, or property occurs to a close approximation, such as accounting for typical tolerance levels or variability of the examples described herein.

[0029] As used herein, the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint. The degree of flexibility of this term can be dictated by the particular variable and would be within the knowledge of those skilled in the art to determine based on experience and the associated description herein. For example, in one aspect, the degree of flexibility can be within about ±10% of the numerical value. In another aspect, the degree of flexibility can be within about ±5% of the numerical value. In a further aspect, the degree of flexibility can be within about ±2%, ±1%, or ±0.05%, of the numerical value.

[0030] Generally herein, the term “or” includes “and” and “and / or.”

[0031] As used herein, a plurality of compounds or steps may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.

[0032] The compounds of the invention may be useful in a free acid form, a free base form, in the form of pharmaceutically acceptable salts, pharmaceutically acceptable hydrates, pharmaceutically acceptable esters, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and in the form of pharmaceutically acceptable stereoisomers. These forms are all within the scope of the invention.Attorney Docket No. 1194MS-540WO1In practice, the use of these forms amounts to use of the neutral compound.

[0033] “Pharmaceutically acceptable salt”, “hydrate”, “ester” or “solvate” refers to a salt, hydrate, ester, or solvate of the inventive compounds which possesses the desired pharmacological activity and which is neither biologically nor otherwise undesirable. Organic acids can be used to produce salts, hydrates, esters, or solvates such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, p-toluenesulfonate, bisulfate, sulfamate, sulfate, naphthylate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, tosylate and undecanoate.Inorganic acids can be used to produce salts, hydrates, esters, or solvates such as hydrochloride, hydrobromide, hydroiodide, and thiocyanate. Other pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, phosphate, tartrate, fumarate, maleate, oxalate, acetate, propionate, succinate, mandelate, mesylate, besylate and tosylate.

[0034] Salts, hydrates, esters, or solvates may also be formed with organic bases. Pharmaceutically acceptable base addition salts of acidic compounds may be formed with organic and inorganic bases by conventional methods. For example, alkali metal and alkaline earth metal hydroxides, carbonates and bicarbonates such as sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, sodium bicarbonate, magnesium carbonate and the like, ammonia, primary, secondary and tertiary amines and the like. Also aluminum salts of the instant compounds may be obtained by treating the corresponding sodium salt with an appropriate aluminum complex such as, for example, aluminum chloride hexahydrate, and the like. Non-toxic organic bases include, but are not limited to, triethylamine, butylamine, piperazine, and tri(hydroxymethyl)-methylamine. Examples of suitable base salts, hydrates, esters, or solvates include hydroxides, carbonates, and bicarbonates of ammonia, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium andAttorney Docket No. 1194MS-540WO1 magnesium salts, aluminum salts, and zinc salts. Organic bases suitable for the formation of pharmaceutically acceptable base addition salts, hydrates, esters, or solvates of the compounds of the present invention include those that are non-toxic and strong enough to form such salts, hydrates, esters, or solvates. For purposes of illustration, the class of such organic bases may include mono-, di-, and trialkylamines, such as methylamine, dimethylamine, triethylamine and dicyclohexylamine; mono-, di- or trihydroxy alkylamines, such as mono-, di-, and triethanolamine; amino acids, such as arginine and lysine; guanidine; N-methyl-glucosamine; N- methyl-glucamine; L-glutamine; N-methyl-piperazine; morpholine; ethylenediamine; N-benzyl- phenethylamine; (trihydroxy-methyl)aminoethane; and the like. See, for example, “Pharmaceutical Salts,” J. Pharm. Sci., 66:1, 1-19 (1977). Accordingly, basic nitrogencontaining groups can be quaternized with agents including: lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as benzyl and phenethyl bromides.

[0035] The salts, hydrates, esters, or solvates of the basic compounds may be prepared either by dissolving the free base of a oxathiazin-like compound in an aqueous or an, aqueous alcohol solution or other suitable solvent containing the appropriate acid or base, and isolating the salt by evaporating the solution. Alternatively, the free base of the oxathiazin-like compound may be reacted with an acid, as well as reacting the oxathiazin-like compound having an acid group thereon with a base, such that the reactions are in an organic solvent, in which case the salt separates directly or can be obtained by concentrating the solution.

[0036] “Pharmaceutically acceptable prodrug” refers to a derivative of the inventive compounds which undergoes biotransformation prior to exhibiting its pharmacological effect(s). The prodrug is formulated with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and / or decreased sideAttorney Docket No. 1194MS-540WO1 effects (e.g., toxicity). The prodrug can be readily prepared from the inventive compounds using methods known in the art, such as those described by Burger's Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982 (1995). For example, the inventive compounds can be transformed into prodrugs by converting one or more of the hydroxy or carboxy groups into esters. Further, N-protected versions of the inventive compounds are also included as non-limiting examples of pharmaceutically acceptable prodrugs of the inventive compounds.

[0037] “Pharmaceutically acceptable metabolite” refers to drugs that have undergone a metabolic transformation. After entry into the body, most drugs are substrates for chemical reactions that may change their physical properties and biologic effects. These metabolic conversions, which usually affect the polarity of the compound, alter the way in which drugs are distributed in and excreted from the body. However, in some cases, metabolism of a drug is required for therapeutic effect. For example, anticancer drugs of the antimetabolite class must be converted to their active forms after they have been transported into a cancer cell. Since must drugs undergo metabolic transformation of some kind, the biochemical reactions that play a role in drug metabolism may be numerous and diverse. The main site of drug metabolism is the liver, although other tissues may also participate.

[0038] An in vivo cleavable linker or group refers to a moiety capable of undergoing cleavage in a particular in vivo environment, such as high or low pH, high or low reduction potential, high or low oxidation potential, or presence of an enzyme. Examples of in vivo cleavable linkers or groups include, but are not limited to, enzymatically cleavable groups (e.g., peptides, phosphates, sugars, lipids, esters), pH-sensitive linkers (e.g., hydrazones, acetals, maleic acid derivatives), redox-sensitive linkers (e.g., disulfides), and oxidation-sensitive linkers (e.g., thioethers, boronates).

[0039] A leaving group in aqueous solution refers to a group capable of spontaneous detachment from a molecule under aqueous conditions. Examples of leaving groups include, butAttorney Docket No. 1194MS-540WO1 are not limited to, halides, sulfonates, phosphonates, and trityl groups.

[0040] Furthermore, certain compositions, concentrations, dosage regimens, dosage amounts, syndromes or conditions, steps, or the like may be discussed in the context of one specific aspect. It is understood that this is merely for convenience, and such disclosure is equally applicable to other aspects found herein. For example, a list of method steps, active agents, kits or compositions described with respect to a method of administering an anti-c-MYC agent of the present disclosure would find direct support for aspects related to method steps, active agents, kits or compositions of, e.g., the following: treating, preventing, inhibiting or reducing at least one sign or symptom of a disease, disorder or condition caused by or associated with c-MYC activity; treating, preventing, inhibiting or reducing at least one side effect of a drug administered to a subject suffering from a disease, disorder or condition caused by or associated with c-MYC activity; treating, preventing, inhibiting or reducing the incidence of a sign or symptom of a disease, disorder or condition caused by or associated with c-MYC activity; modulating vascularization; regulating vascularization; modulating angiogenesis; and regulating c-MYC activity, even if those method steps, active agents, kits or compositions are not re-listed in the context of that aspect in the specification.

[0041] The term “treating” or “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilizing (i.e. not worsening) the state of disease, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. “Treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In addition to being useful as methods of treatment, the methods described herein may be useful for the prevention or prophylaxis of disease. As used herein, the term “treating” mayAttorney Docket No. 1194MS-540WO1 refer to any administration of a compound of the present invention and includes: (i) preventing or inhibiting the disease in a mammal, e.g., a human, that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and / or symptomatology); or (ii) ameliorating the disease in a mammal, e.g., a human that is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and / or symptomatology). The term “controlling” includes preventing, treating, eradicating, ameliorating or otherwise reducing the severity of the condition being controlled.

[0042] Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 0.01 to 2.0” should be interpreted to include not only the explicitly recited values of about 0.01 to about 2.0, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 0.5, 0.7, and 1.5, and sub-ranges such as from 0.5 to 1.7, 0.7 to 1.5, and from 1.0 to 1.5, etc. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described. Additionally, it is noted that all percentages are in weight, unless specified otherwise.

[0043] In understanding the scope of the present disclosure, the terms “including” or “comprising” and their derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms “including”, “having” and their derivatives. The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features,Attorney Docket No. 1194MS-540WO1 elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The term “consisting essentially of’, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and / or steps. It is understood that reference to any one of these transition terms (i.e. “comprising,” “consisting,” or “consisting essentially”) provides direct support for replacement to any of the other transition term not specifically used. For example, amending a term from “comprising” to “consisting essentially of’ would find direct support due to this definition.

[0044] Some oxathiazin-like compounds are described in PCT / IB2015 / 059741, filed December 17, 2015, which is incorporated herein by reference in its entirety. In certain aspects, oxathiazin-like compounds according to Formula I are utilized according to the invention wherein R is H, an in vivo cleavable linker or group, or a leaving group in aqueous solution, and Ri and R2 are independently, H, alkyl, an aryl, a substituted alkyl, a substituted phenyl, a substituted aryl, or a combination thereof.

[0045] In some aspects, the substituted alkyl, substituted phenyl, or substituted aryl may be substituted with any appropriate molecule including, e.g., one or more halogens or halogencontaining molecules, one or more hydroxyl groups, one or more acyl groups, one or more acyloxy groups, one or more alkoxy groups, one or more aryl groups, one or more carboxy groups, one or more carbonyl groups, one or more alkylcarboxy groups, one or more alkylsufonoxy groups, one or more alkylcarbonyl groups, one or more nitro groups, one or more cyano groups, one or more acylamido groups, one or more phenyl groups, one or more tolyl groups, one or more chlorophenyl groups, one or more alkoxyphenyl groups, one or more halophenyl groups, one or more benzoxazole groups, one or more thiazoline groups, one or more benzimidazole groups, one or more oxazole groups, one or more thiazole groups, one or more indole groups, etc., or a combination thereof. In some aspects, the alkyl or substitutedAttorney Docket No. 1194MS-540WO1 alkyl may be a Cl to C30 alkyl. In some aspects, the alkyl may be branched or unbranched. In some aspects, the aryl may be heterocyclic, polycyclic, or monocyclic.Formula I.

[0046] Exemplary oxathiazin-like compounds include the following:Attorney Docket No. 1194MS-540WO1

[0048] 2296, and isethionic acid hydroxymethylamide.

[0049] In certain aspects, 2250 (Tetrahydrol,4,5-oxathiazin-4-dioxide or 1,4,5- oxathiazan-4-dioxide) is used for inhibiting c-MYC and for treating, preventing, inhibiting or reducing at least one sign or symptom of a disease, disorder, condition, symptom caused by or associated with c-MYC activity in accordance with the disclosure herein, e.g., including but not limited to a disease, disorder, condition or symptom caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy.

[0050] In certain aspects, the present disclosure provides isethionic acid hydroxymethylamide as a chemical compound, in a composition, and for administration according to the methods of the present disclosure.

[0051] In certain aspects, the invention also relates to compositions, e.g., pharmaceutical compositions, containing the compounds, complexes, or conjugates described herein, including pharmaceutically acceptable solutions thereof, as well as administrable compositions, kits, medical devices, and pharmaceutical containers containing the compositions of the present disclosure.

[0052] The terms “effective amount” or “therapeutically effective amount” describedAttorney Docket No. 1194MS-540WO1 herein means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. In one example, the therapeutically effective amount comprises about 0.0001 to about 10,000 mg / kg, about 0.001 mg / kg to about 5,000 mg / kg, about 0.01 mg / kg to about 1,000 mg / kg, about 0.05 mg / kg to about 750 mg / kg, about 0.1 mg / kg to about 600 mg / kg, about 1 mg / kg to about 500 mg / kg, about 10 mg / kg to about 400 mg / kg, about 20 mg / kg to about 300 mg / kg, about 200 mg / kg to about 500 mg / kg, about 300 mg / kg to about 400 mg / kg, about 250 mg / kg, 300 mg / kg, 400 mg / kg, 420 mg / kg, 450 mg / kg, about 500 mg / kg, or an dosage amount or range within any of the disclosed ranges of body weight of the subject.

[0053] The terms “administration of’ or “administering a” compound as used herein should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body, e.g., intravenously, subcutaneously, intramuscularly, topically, orally, intraperitoneally, ophthalmically, by intravitreal injection, intrathecally, intranasally, intrapulmonary, transdermally, intraocularly, by inhalation, transtracheally, intravitreally, or a combination thereof. In some aspects, a compound of the invention may be administered in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as intravenous (IV), intramuscular (IM), or intraperitoneal (IP), intranasal, and the like; enteral or parenteral, transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.

[0054] Depending upon the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically active materials may be included, which do not substantially interfereAttorney Docket No. 1194MS-540WO1 with the activity of the one or more oxathiazin-like compounds.

[0055] As used herein the term “intravenous administration” includes injection, infusion, and other modes of intravenous administration.

[0056] The term “pharmaceutically acceptable” as used herein to describe a carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0057] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure alone or in combination with at least one second active agent. For example, in some aspects, the present disclosure includes administering one or more compounds of the present disclosure with an anti-angiogenesis agent, anti-autoimmune agent, and / or anti-neoplastic agent to a subject in need thereof.

[0058] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to induce generation of reactive oxygen species (ROS) or increase a level of ROS in cells of a subject. In one aspect, the present disclosure includes a method of increasing a level of ROS by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, or about 200% in cells of a subject. In one aspect, the present disclosure includes a method of increasing a level of ROS by about 1.2 fold, about 1.4 fold, about 1.6 fold, about 1.8 fold, about 2 fold, about 2.2 fold, about 2.4 fold, about 2.6 fold, about 2.8 fold, or about 3 fold in cells of a subject.

[0059] In one aspect, the present disclosure includes increasing a level of ROS in a subject’s cells by administering one or more compounds of the present disclosure to the subject to treat, prevent, inhibit or reduce at least one sign or symptom of a disease, disorder or condition, e.g., including but not limited to a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessiveAttorney Docket No. 1194MS-540WO1 angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy. In one aspect, the present disclosure includes increasing a level of ROS in a subject’s cells by administering one or more compounds of the present disclosure to the subject to treat a cancer.

[0060] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to inhibit NF-KB activity in a subject in need thereof. In one aspect, the present disclosure includes a method of inhibiting about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of NF-KB activity in cells of a subject.

[0061] In one aspect, the present disclosure includes inhibiting NF-KB activity by administering one or more compounds of the present disclosure to a subject in need thereof to treat, prevent, inhibit or reduce at least one sign or symptom of a disease, disorder or condition caused by or associated with NF-KB activity, e.g., including but not limited to a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy. In one aspect, the present disclosure includes inhibiting NF-KB activity by administering one or more compounds of the present disclosure to a subject in need thereof to treat a cancer.

[0062] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to reduce a level of NF-KB in a subject in need thereof. In one aspect, the present disclosure includes a method of reducing a level of NF-KB by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% in cells of a subject.

[0063] In one aspect, the present disclosure includes reducing a level of NF-KB activity by administering one or more compounds of the present disclosure to a subject in need thereof toAttorney Docket No. 1194MS-540WO1 treat, prevent, inhibit or reduce at least one sign or symptom of a disease, disorder or condition caused by or associated with NF-KB activity, e.g., including but not limited to a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy. In one aspect, the present disclosure includes reducing a level of NF-KB by administering one or more compounds of the present disclosure to a subject in need thereof to treat a cancer.

[0064] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to increase phosphorylation of one or more proteins. For example, in some aspects, the present disclosure includes administering one or more compounds of the present disclosure to increase phosphorylation of AMPK, ACC, or Raptor, in cells of a subject. In one aspect, the present disclosure includes a method of increasing phosphorylation of one or more proteins by about 20%, about 40%, about 60%, about 80%, about 100%, about 120%, about 140%, about 160%, about 180%, about 200%, about 250%, about 300%, about 350%, about 400%, about 450%, or about 500% in cells of a subject. In one aspect, the present disclosure includes a method of increasing phosphorylation of one or more proteins by about 1.2 fold, about 1.4 fold, about 1.6 fold, about 1.8 fold, about 2 fold, about 2.2 fold, about 2.4 fold, about 2.6 fold, about 2.8 fold, about 3 fold, about 3.5 fold, about 4 fold, about 4.5 fold, or about 5 fold in cells of a subject. In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to increase phosphorylation of AMPK. In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to increase phosphorylation of ACC. In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to increase phosphorylation of Raptor.

[0065] In one aspect, the present disclosure includes increasing phosphorylation of oneAttorney Docket No. 1194MS-540WO1 or more proteins, e.g., including but not limited to AMPK, ACC, or Raptor, in a subject’s cells by administering one or more compounds of the present disclosure to the subject to treat, prevent, inhibit or reduce at least one sign or symptom of a disease, disorder or condition, e.g., including but not limited to a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy. In one aspect, the present disclosure includes increasing phosphorylation of one or more proteins, e.g., including but not limited to AMPK, ACC, or Raptor, in a subject’s cells by administering one or more compounds of the present disclosure to the subject to treat a cancer.

[0066] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to increase a level of p53 in cells of a subject. In one aspect, the present disclosure includes a method of increasing a level of p53 by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 150%, or about 200% in cells of a subject. In one aspect, the present disclosure includes a method of increasing a level of p53 by about 1.2 fold, about 1.3 fold, about 1.4 fold, about 1.5 fold, about 1.6 fold, about 1.7 fold, about 1.8 fold, about 1.9 fold, or about 2 fold in cells of a subject.

[0067] In one aspect, the present disclosure includes increasing a level of p53 in a subject’s cells by administering one or more compounds of the present disclosure to the subject to treat, prevent, inhibit or reduce at least one sign or symptom of a disease, disorder or condition caused by or associated with p53 activity, e.g., including but not limited to a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immuneAttorney Docket No. 1194MS-540WO1 reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy. In one aspect, the present disclosure includes increasing a level of p53 in a subject’s cells by administering one or more compounds of the present disclosure to the subject to treat a cancer.

[0068] A multitude of cMYC-driven downstream genes are affected by treatment of cancer cells with the compounds of the present disclosure. This includes the inhibition of the cell cycle by GP-2250 as demonstrated by the dose- and time-dependent downregulation of the expression of Cyclin D2 as shown in Fig. 8 and described in Example 10.

[0069] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to decrease a level of one or more proteins. For example, in some aspects, the present disclosure includes administering one or more compounds of the present disclosure to decrease a level of Cyclin DI, Cyclin D2, mTOR, Akt, or Bcl2, in cells of a subject. In one aspect, the present disclosure includes a method of decreasing a level of one or more proteins by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%, in cells of a subject. In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to decrease a level of Cyclin DI. In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to decrease a level of Cyclin D2. In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to decrease a level of mTOR. In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to decrease a level of Akt. In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to decrease a level of Bcl2.

[0070] In one aspect, the present disclosure includes decreasing a level of one or more proteins, e.g., including but not limited to Cyclin DI, Cyclin D2, mTOR, Akt, or Bcl2, in a subject’s cells by administering one or more compounds of the present disclosure to the subject to treat, prevent, inhibit or reduce at least one sign or symptom of a disease, disorder orAttorney Docket No. 1194MS-540WO1 condition, e.g., including but not limited to a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy. In one aspect, the present disclosure includes decreasing a level of one or more proteins, e.g., including but not limited to Cyclin DI, Cyclin D2, mTOR, Akt, or Bcl2, in a subject’s cells by administering one or more compounds of the present disclosure to the subject to treat a cancer.

[0071] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to inhibit c-MYC activity in a subject in need thereof. In one aspect, the present disclosure includes a method of inhibiting about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100% of c-MYC activity in cells of a subject.

[0072] In one aspect, the present disclosure includes inhibiting c-MYC activity by administering one or more compounds of the present disclosure to a subject in need thereof to treat, prevent, inhibit or reduce at least one sign or symptom of a disease, disorder or condition caused by or associated with c-MYC activity, e.g., including but not limited to a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy.

[0073] In some aspects, the present disclosure includes inhibiting c-MYC activity by administering one or more compounds of the present disclosure to a subject in need thereof to irreversibly inhibit c-MYC. In some aspects, the present disclosure includes inhibiting c-MYC activity by administering one or more compounds of the present disclosure to a subject in needAttorney Docket No. 1194MS-540WO1 thereof to reduce, inhibit, prevent and / or eliminate cancer stem cells (CSCs). In some aspects, the present disclosure includes inhibiting c-MYC activity by administering one or more compounds of the present disclosure to a subject in need thereof without interfering with targeted cancer cell cytotoxicity in immune therapies including but not limited to immune checkpoint proteins, and T-cell engaging therapies, e.g., CAR-T and bispecific therapies.

[0074] In some aspects, administering one or more compounds of the present disclosure inhibits c-MYC activity by interfering with the binding of c-MYC to DNA. In some aspects, administering one or more compounds of the present disclosure inhibits c-MYC activity by destabilizing c-MYC structure. In some aspects, administering one or more compounds of the present disclosure inhibits c-MYC activity by promoting its degradation. In some aspects, administering one or more compounds of the present disclosure inhibits c-MYC activity by interfering with the binding of c-MYC to myc-associated factor X (MAX).

[0075] In one aspect, the present disclosure includes administering one or more compounds of the present disclosure to reduce a level of c-MYC in a subject in need thereof. In one aspect, the present disclosure includes a method of reducing the level of c-MYC in cells of a subject by about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

[0076] In one aspect, the present disclosure includes reducing a level of c-MYC by administering one or more compounds of the present disclosure to a subject in need thereof to treat, prevent, inhibit or reduce at least one sign or symptom of a disease, disorder or condition caused by or associated with c-MYC activity, e.g., including but not limited to a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy.Attorney Docket No. 1194MS-540WO1

[0077] In some aspects, the present disclosure includes methods and compositions for treating a subject having cancer, autoimmune disease, angiogenesis or other disease, disorder, condition or symptom disclosed herein, comprising selecting a subject having cancer, autoimmune disease, angiogenesis or other disease, disorder, condition or symptom disclosed herein, associated with c-MYC and administering to the selected subject one or more c-MYC inhibitors comprising oxathiazine-like compounds of the present disclosure.

[0078] In some aspects, the present disclosure includes methods and compositions for treating cancer, autoimmune disease, neovascularization, and / or excessive angiogenesis associated with c-MYC in a subject comprising administering to the subject one of more c-MYC inhibitors comprising oxathiazine-like compounds of the present disclosure.

[0079] In some aspects, the present disclosure includes methods for selecting a subject having cancer, autoimmune disease, neovascularization, and / or excessive angiogenesis associated with c-MYC for treatment with one or more oxathiazine-like compounds comprising detecting c-MYC in a biological sample of the subject and selecting the subject for treatment with one of more oxathiazine-like compounds of the present disclosure. In some aspects, the cancer, autoimmune disease, neovascularization, and / or excessive angiogenesis associated with c-MYC in a subject is determined by isolating a sample of cells or biological sample from a subject and assessing c-MYC activity in the cells or biological sample.

[0080] In some aspects, the present disclosure includes methods for screening for c-MYC inhibition by one or more oxathiazine-like compounds by contacting a cell or biological sample containing c-MYC with one or more oxathiazine-like compounds and determining whether C- MYC is inhibited in the cell or biological sample and selecting from the one or more oxathiazine-like compounds at least one compound that inhibits C-MYC. In some aspects, a C- MYC inhibition of above a threshold (e.g., by at least 30% over control) indicates that the compound has anticancer, anti-autoimmune, anti-neovascularization, and / or anti-excessive angiogenesis activity.Attorney Docket No. 1194MS-540WO1

[0081] In some aspects, the present disclosure includes methods for determining if C- MYC is inhibited by one or more oxathiazine- like compounds by contacting a cell or biological sample containing C-MYC with one or more oxathiazine-like compounds and determining whether C-MYC is inhibited in the cell or biological sample.

[0082] In some aspects, the present disclosure includes methods for determining if a level of C-MYC is reduced by one or more oxathiazine-like compounds by contacting a cell or biological sample containing C-MYC with one or more oxathiazine-like compounds and determining whether the level of C-MYC is reduced in the cell or biological sample.

[0083] In some aspects, the present disclosure includes methods of evaluating anticancer, autoimmune, neovascularization, and / or excessive angiogenesis properties of oxathiazine-like compounds for treating cancer, autoimmune disease, neovascularization, and / or excessive angiogenesis comprising contacting a cell or biological sample with an oxathiazine-like compound and determining whether C-MYC is inhibited or a level of C-MYC is reduced in the cell or biological sample, wherein C-MYC inhibition or reduction in the level of C-MYC by the oxathiazine-like compound indicates that the oxathiazine-like compound is useful for treating cancer, autoimmune diseases, neovascularization, and / or excessive angiogenesis.

[0084] In some aspects, the present disclosure includes methods of evaluating anticancer, autoimmune, neovascularization, and / or excessive angiogenesis properties of oxathiazine-like compounds for treating cancer, autoimmune disease, neovascularization, and / or excessive angiogenesis comprising contacting a cell or biological sample with an oxathiazine-like compound and determining whether NF-KB is inhibited or a level of Cyclin DI, Cyclin D2, Akt, mTOR, or Bcl2 is reduced in the cell or biological sample, wherein NF-KB inhibition or reduction in the level of Cyclin DI, Cyclin D2, Akt, mTOR, or Bcl2 by the oxathiazine-like compound indicates that the oxathiazine-like compound is useful for treating cancer, autoimmune diseases, neovascularization, and / or excessive angiogenesis.

[0085] In some aspects, the present disclosure includes methods of evaluating anticancer,Attorney Docket No. 1194MS-540WO1 autoimmune, neovascularization, and / or excessive angiogenesis properties of oxathiazine-like compounds for treating cancer, autoimmune disease, neovascularization, and / or excessive angiogenesis comprising contacting a cell or biological sample with an oxathiazine-like compound and determining whether a level of phosphorylated AMPK (pAMPK), phosphorylated ACC (pACC), phosphorylated Raptor (pRaptor), or p53 is increased in the cell or biological sample, wherein an increase in the level of pAMPK, pACC, pRaptor, or p53 by the oxathiazinelike compound indicates that the oxathiazine-like compound is useful for treating cancer, autoimmune diseases, neovascularization, and / or excessive angiogenesis.

[0086] Anti-C-MYC agents of the present disclosure may be administered to subjects at risk of suffering from or suffering from a variety of diseases, disorders and conditions. Such diseases, disorders and conditions may be characterized by neovascularization and / or excessive angiogenesis. The present disclosure also provides methods and compositions for modulating and regulating vascularization, modulating and regulating angiogenesis, and preventing, treating, inhibiting, or reducing neovascularization and / or excessive angiogenesis also referred to as angiogenesis-associated or neovascularization-associated diseases, disorders and conditions.Non-limiting examples of such diseases, disorders and conditions include one or more of tumors, cancers including, but not limited to carcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, a metastatic solid tumor, and mixed-type cancers, skin diseases (including, but are not limited to, psoriasis, telangiectasia, wound granularization, scleroderma, neovascularization as a consequence of infection (e.g., cat scratch disease, bacterial ulceration, etc.)), macular degeneration or age-related blindness, diabetic ulcers, chronic ulcers and wounds, stroke, traumatic brain injury, neovascularization of the retina, neovascularization of the cornea (such as that caused by trachoma, infections, inflammation, transplantations or trauma), diabetic retinopathy, diabetic retinal edema, diabetic macula edema, ischemic retinopathy, hypertensive retinopathy, occlusive retinopathy, retinopathy of prematurity, neovascularization subsequent to trauma, neovascularization subsequent to infection, neovascularization subsequent toAttorney Docket No. 1194MS-540WO1 transplantation, neovascularization subsequent to retinal detachment or retinal degeneration, neovascular glaucoma, anterior chamber and / or anterior chamber angle neovascularization, choroidal neovascularization (CNV), subretinal neovascularization, retrolental fibroplasias, ocular histoplasmosis syndrome, myopic degeneration, angioid streaks, uveitis, rubeosis, retrolental fibroplasias, ocular histoplasmosis, and idiopathic central serous chorioretinopathy, amyotrophic lateral sclerosis, sarcoidosis, scleroderma, lupus, Parkinson’s disease, sclerosis, Stevens-Johnson syndrome, neoplasia, Von Willebrand disease, vasculitis, and Kawasaki disease.

[0087] The present disclosure also provides methods and compositions for treating subjects suffering from cardiovascular diseases including but not limited to atherosclerosis, restenosis, atheroma, and haemangioma Atherosclerosis is a form of chronic vascular injury in which some of the normal vascular smooth cells (VSMC) in the artery wall change their nature and develop dense networks of capillaries in atherosclerotic plaques. These fragile microvessels can cause hemorrhages, leading to blood clotting, with a subsequent decreased blood flow to the heart muscle and heart attack. Restenosis typically occurs after coronary artery bypass surgery, endarterectomy, and heart transplantation, and particularly after heart balloon angioplasty, atherectomy, laser ablation or endovascular stenting. It involves extensive growth of microvessels. By inhibiting angiogenesis in the cardiovascular tissue, the methods provided herein are useful for treating these cardiovascular diseases.

[0088] In one aspect, the present disclosure relates to treating macular degeneration. In particular, an ophthalmic formulation containing the compounds of the present disclosure are administered to a subject in need thereof. Ophthalmic indications according to the present disclosure include all forms of diabetic retinopathy in people with or without diabetic macular edema and specifically diabetic macular edema. Diabetic retinopathy is a serious condition that affects millions of people. In one aspect, compositions of the present disclosure are administered by intravitreal injection.Attorney Docket No. 1194MS-540WO1

[0089] In some aspects, the at least one sign or symptom may include rash, muscle pain, joint pain, fatigue, anemia, inflammation, abdominal pain, abdominal bloating, diarrhea, nausea, acid reflux, weight gain, fever, ongoing headaches, bleeding complications (e.g., hemorrhage), hypertension, hypotension, low blood counts, tumor-growth, cachexia, light sensitivity, eye redness, eye irritation, or a combination thereof.

[0090] In one aspect, the present disclosure includes preventing, inhibiting or reducing at least one side effect of a drug administered to a subject suffering from disease, disorder or condition caused by or associated with neovascularization and / or excessive angiogenesis by inhibiting C-MYC activity by co-administering one or more oxathiazine-like compounds to the subject. In some aspects, the at least one side effect may include one or more of bleeding complications (e.g., hemorrhage), hypertension, diarrhea, fatigue, low blood counts, reduced wound healing, itchy, dry or flaky skin, dry or watery eyes, pain, headaches, rash, dizziness, weight loss, hair loss, swelling, unusual bruising, seizure, muscle weakness, numbness, infection, fever, chills, aches, pain, poor appetite, change in weight joint pain / swelling, or a combination thereof.

[0091] In one aspect, the present disclosure includes methods and compositions for increasing the therapeutic index of a chemotherapeutic drug by (e.g., lowering toxicity, increasing tumor uptake of the drug, increasing efficacy, etc.) inhibiting C-MYC activity by coadministering one or more oxathiazine-like compounds of the present disclosure with the chemotherapeutic drug. In some aspects, the chemotherapeutic drug may include trastuzumab, alemtuzumab, bevacizumab, blinatumomab, brentuximab vedotin, infliximab, eculizumab, certolizumab, daclizumab, cetuximab, denosumab, dinutuximab, ibritumomab tiuxetan, ipilimumab, nivolumab, obinutuzumab, ofatumumab, panitumumab, pembrolizumab, pertuzumab, rituximab, trastuzumab. In some aspects, the combination increases the therapeutic index by rendering the co-therapy less toxic. The lower toxicity allows more chemotherapeutic drug(s) to be delivered while maintaining acceptable side effects. It is also contemplated that theAttorney Docket No. 1194MS-540WO1 co-therapy is more efficacious and, as such, less chemotherapeutic drug can be used to get the same results provided by previous compositions.

[0092] The phrases “co-administering” or “administering in combination” as used herein mean that two (or more) agents are administered in temporal juxtaposition. The coadministration or combination may including administering the two agents in a single formulation, or by administering the two agents separately but simultaneously, or separately sequentially. For example, in general the two agents are co- administered within the time range of 6-168 hours. In this case, the agents may be administered in either order, i.e. the chemotherapeutic drug may be administered first, or the one or more oxathiazine-like compounds of the present disclosure may be administered first. In some aspects, the two agents are co-administered in a single formulation, or are co-administered sequentially and separately.

[0093] In one aspect, this disclosure relates to a method of reducing chemotherapy drug- related toxicity in a patient treated with a chemotherapy drug and at risk of such toxicity, which method comprises treating said patient with one or more oxathiazine-like compounds and a chemotherapy drug, such that said patient has reduced risk of chemotherapy drug-related toxicity. In one embodiment, the chemotherapy drug-related toxicity is cardiotoxicity, nephrotoxicity, hepatotoxicity, pulmonary toxicity, dermatologic toxicity, or gastrointestinal toxicity. For example, some chemotherapeutic drugs may cause direct injury to the heart (either acute or chronic), including anthracyclines. Chemotherapy drugs, including cisplatin, cyclophosphamide, and ifosfamide, produce urinary tract / kidney toxicity. Drugs with pulmonary toxicity, including bleomycin, can cause severe pulmonary effects. Dermatologic toxicity is also common with chemotherapeutic drugs, and include transient rash (carmustine, cytarabine, gemcitabine, asparaginase, and procarbazine), photosensitivity (Mitomycin, 5-FU, methotrexate, vinblastine, and dacarbazine), dermatitis, hyperpigmentation, urticaria, nail changes, alopecia, and radiation recall. Gastrointestinal toxicity, including stomatitis or diarrhea, is also common.

[0094] In some aspects, the patient suffers from cancers or tumors including, but notAttorney Docket No. 1194MS-540WO1 limited to biliary tract cancer; brain cancer, including glioblastomas and medulloblastomas; breast cancer; triple negative breast cancer; uterine cancer; tubal cancer; cervical cancer; choriocarcinoma; colon cancer; bladder cancer; endometrial cancer; retinoblastoma; vaginal cancer; vulvar cancer; esophageal cancer; mouth cancer; gastric cancer; kidney cancer; hematological neoplasms, including acute lymphocytic and myelogenous leukemia; multiple myeloma; AIDS-associated leukemias and adult T-cell leukemia lymphoma; intraepithelial neoplasms, including Bowen's disease and Paget's disease; liver cancer (hepatocarcinoma); lung cancer; head or neck cancers or oral cancers (mouth, throat, esophageal, nasopharyngeal, jaw, tonsil, nasal, lip, salivary gland, tongue, etc.); lymphomas, including Hodgkin's disease and lymphocytic lymphomas; neuroblastomas; neuroendocrine tumors; oral cancer, including squamous cell carcinoma; adrenal cancer; anal cancer; angiosarcoma; appendix cancer; bile duct cancer; bone cancer; carcinoid tumors; soft tissue sarcoma; rhabdomyosarcoma; eye cancer; ovarian cancer, including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells, and fallopian tube cancer; gallbladder cancer; pancreatic cancer; prostate cancer; rectal cancer; sarcomas, including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma; skin cancer, including melanoma, Kaposi's sarcoma, basocellular cancer and squamous cell cancer; testicular cancer, including germinal tumors (seminoma, non-seminoma[teratomas, choriocarcinomas]), stromal tumors and germ cell tumors; penile cancer; hemangioendothelioma; gastrointestinal cancer; ureteral cancer; urethral cancer; spinal cancer; pituitary gland cancer; primary central nervous system (CNS) lymphoma; thyroid cancer, including thyroid adenocarcinoma and medullar carcinoma; and renal cancer including adenocarcinoma and Wilms tumor. In some aspects, cancers or tumors include breast cancer, prostate cancer, colorectal cancer, lymphoma, multiple myeloma, and melanoma.

[0095] Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeuticallyAttorney Docket No. 1194MS-540WO1 effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50.

[0096] As used herein, the term “therapeutic index” with regard to a chemotherapeutic drug indicates safety of the chemotherapeutic drug. In some aspects, the therapeutic index can include a comparison of the amount of a therapeutic agent that causes the therapeutic effect (e.g., killing cancer cells) to the amount of the therapeutic agent that causes toxicity (e.g., liver toxicity). It is contemplated that according to certain embodiments an improved therapeutic index can occur using the compositions and / or methods described herein, including without limitation when: (1) the dosage of chemotherapeutic drug is increased above the current therapeutic dosages; (2) the dosage of chemotherapeutic drug remains the same as the current therapeutic dosages; or (3) the dosage of chemotherapeutic drug is decreased below the current therapeutic dosages. In some embodiments, the compositions and methods, including the scenarios in this paragraph can elicit improved or similar therapeutic effect as seen with the current therapeutic dosages with no worse, fewer, or no toxicities.

[0097] In one aspect, the present disclosure includes a method of inhibiting C-MYC activity or reducing a level of C-MYC by administering one or more compounds of the present disclosure to a subject in need thereof to down-regulate vascularization by administering one or more oxathiazine-like compounds to a subject, thereby preventing neovascularization in the subject.

[0098] In one aspect, the present disclosure includes a method of inhibiting C-MYC activity or reducing a level of C-MYC by administering one or more compounds of the present disclosure to a subject in need thereof to down-regulate angiogenesis by administering one or more oxathiazine-like compounds to a subject, thereby preventing undesired excessive angiogenesis in the subject.

[0099] In one aspect, the subject is treated with one or more oxathiazine-like compounds, or a combination thereof, administered intravenously, orally or a combination thereof. In oneAttorney Docket No. 1194MS-540WO1 aspect, the patient is treated with 2250 (also referred to as “compound 2250”, “C-2250”, “misetionamide”, or “GP-2250”) administered intravenously, orally or a combination thereof.

[0100] In one aspect, the subject is administered one or more oxathiazine-like compounds or a combination thereof in conjunction with administration of one or more therapeutic drugs for treating subjects with a disease, disorder or condition caused by or associated with impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy, e.g., anti- VEGF antibodies, bevacizumab, ranibizumab, brolucizumab, lapatinib, sunitinib, sorafenib, axitinib, cabozantinib, lenvatinib, ponatinib, ramucirumab, reorafenib, vandetanib, pazopanib, pegaptanib, bevasriranib, aflibercept, thiazolidinediones, conbercept, and lampalizumab, corticosteroids, immunosuppressants, e.g., cyclosporine, tacrolimus, anti-inflammatory drugs, e.g., dimethyl fumarate, sphingosine- 1 -phosphate (SIP) receptor modulators, e.g., siponimod, fingolimod, ceralifimod, ozanimod, ponesimod, autoimmune modulator peptides, e.g., glatiramer acetate and similar random-sized peptides, biologic drugs, e.g., antibodies, fusion proteins, and interferon-based drugs.

[0101] In some aspects, the present disclosure includes administering one or more oxathiazine-like compounds in combination with one or more of tocilizumab, antihistamines, antipyretics, anti-inflammatory compounds, corticosteroids, glucocorticoids, TNF-inhibitors (e.g., etanercept), siltuximab, T cell-depleting antibody therapies such as alemtuzumab and antithymocyte globulins (ATG), IL-lR-based inhibitors (anakinra), ibrutinib and cyclophosphamide.

[0102] Compounds according to the invention can be administered by any suitable method. Solid dosage forms for oral administration include capsules, tablets, pills, powders, orally-disintegrating tablets, and granules. In such solid dosage forms, the provided compositionAttorney Docket No. 1194MS-540WO1 is mixed with at least one inert, pharmaceutically acceptable excipient and / or fillers or extenders(e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid), binders (e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), humectants (e.g., glycerol), disintegrating agents (e.g., agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution retarding agents (e.g., paraffin), absorption accelerators (e.g., quaternary ammonium compounds), wetting agents (e.g., cetyl alcohol and glycerol monostearate), absorbents (e.g., kaolin and bentonite clay), and lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

[0103] Solid compositions of a similar type may be employed as fillers in soft and / or hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the provided composition(s) only in, or targeting, a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0104] In certain aspects, capsules may contain an excipient formulation containing one or more of hydroxypropyl methylcellulose (HPMC), gelatin, meglumine, and fish gelatin. In certain aspects, a capsule may contain compound 2250 in combination with taurolidine and / or taurultam. The capsule may optionally further contain one or more of lycopene, ellagic acid (polyphenol), curcumin, piperine, delphinidin, resveratrol, isothiocyanates such as sulforaphane,Attorney Docket No. 1194MS-540WO1 capsaicin, and piperlongumine.

[0105] When used in the form of microparticles or nanoparticles, the compounds of the claimed invention may achieve higher blood levels. The present invention includes microparticles and / or nanoparticles of the compounds of the present disclosure in tablet form or encapsulated in capsules.

[0106] In certain aspects, this disclosure relates to administering an oxathiazine-like compound orally to a patient. In some aspects, an oxathiazine-like compound is formulated in capsules or tablets. In certain aspects, oral dosage forms contain between about 50-1000 mg of an oxathiazine-like compound. In certain aspects, oral dosage forms contain between about 100- 500 mg of an oxathiazine-like compound. In certain aspects, oral dosage forms contain between about 200-400 mg of an oxathiazine-like compound. In certain aspects, oral dosage forms contain between about 250-350 mg of an oxathiazine-like compound. In certain aspects, the oxathiazine-like compound is C-2250.

[0107] In some aspects, the oxathiazine-like compound is provided in a composition at a concentration of about 0.01 to about 500 pg / ml. In some aspects, the oxathiazine-like compound is provided in a composition at a concentration of about 0.1 to about 100 pg / ml. In some aspects, the oxathiazine-like compound is provided in a composition at a concentration of about 10 to about 50 pg / ml.

[0108] In some aspects, the oxathiazine-like compound is provided in a composition at a concentration of about 0.001 to about 5 wt. %, about 0.01 to about 3.5 wt.%, about 0.1 to about 3 wt.%, about 0.5 to about 2.5 wt.%, or about 1 to about 2 wt.% . In some aspects, the oxathiazine-like compound is provided in a composition at a concentration of about 0.01 to about 1.5%. In some aspects, the oxathiazine-like compound is provided in a composition at a concentration of about 0.1% to about 1%. In some aspects, the oxathiazine-like compound is provided in a composition at a concentration of about 100 to about 5000 pM, about 250 to about 2500 pM, about 500 to about 2000 pM, about 750 to about 1500 pM, about 1000 to about 1250Attorney Docket No. 1194MS-540WO1IJ M, or any other concentration within the recited ranges.

[0109] In some aspects, the oxathiazine-like compound is provided in a composition in a unit dosage form. As used herein, a “unit dosage form” is a composition containing an amount of oxathiazine-like compound that is suitable for administration to an animal, such as a mammal, e.g., a human subject, in a single dose, according to a good medical practice. These compositions may contain from about 0.1 mg (milligrams) to about 500 mg, for example from about 5 mg to about 350 mg of oxathiazine-like compound. The frequency of treatment with the composition of the invention may be changed to achieve and maintain the desired target plasma level. Thus, non-limiting examples of treatment schedules include daily, twice daily, three times daily, weekly, biweekly, monthly, and combinations thereof. Alternatively, the composition of the invention may also be administered as a continuous infusion or a bolus following by one, two, three or more different continuous infusions, e.g., at different rates and dosages of administered drug, such regimens optionally interrupted by one or more additional bolus injections.

[0110] In certain aspects, one or more oxathiazine-like compounds of the present disclosure are administered to a subject prior to administration of a therapeutic that is expected to lead to impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy in the subject. For example, in one aspect, the one or more oxathiazine-like compounds of the present disclosure are administered about 12 to 96, e.g., 24, 48 or 72, hours prior to administration of a therapeutic that is expected to lead to (e.g., cause or promote, either directly or indirectly) impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis,Attorney Docket No. 1194MS-540WO1 dysfunctional apoptosis of normal cells, and / or impaired autophagy in the subject. In one aspect, the one or more oxathiazine-like compounds of the present disclosure are administered in one or multiple doses prior to administration of a therapeutic that is expected to lead to impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy in the subject. In certain aspects, one or more oxathiazine-like compounds of the present disclosure are administered to a subject concurrently with a therapeutic that is expected to lead to impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy in the subject. In certain aspects, the oxathiazine-like compound is administered to the subject within about 1 to about 24 hours, about 4 to about 18 hours, about 6 to about 15 hours, or about 8 to about 12 hours after administration to the subject of a therapeutic that is expected to promote impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy in the subject.

[0111] In certain aspects, one or more oxathiazine-like compounds of the present disclosure are administered according to a regimen during a period when impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy angiogenesis is expected to occur. For example, in oneAttorney Docket No. 1194MS-540WO1 aspect, the one or more oxathiazine-like compounds of the present disclosure are administered daily, every other day, biweekly, or weekly for the patient’s lifetime, until remission, multiple years, multiple months, a 2 to 12 week period, a 3 to 10 week period, or a 4 to 8 week period, before, during, and / or after administration a therapeutic that is expected to lead to impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, and / or impaired autophagy in the subject.

[0112] In one aspect, the one or more oxathiazine-like compounds are provided in a composition and is administered to a subject in need thereof at a total daily dosage may be about 0.001 g to about 1000 g, e.g., about 0.01 g to about 500 g, 0.1 to 300 g, 0.5 to 200 g, 1 g to 100 g, or any amount within the recited range. The daily dosage may be administered in the form of an orally administrable composition. The daily dosage may be administered in the form of a capsule, a tablet, or a pharmaceutically acceptable solution. The daily dosage may be administered in a form that contains compound 2250 at a concentration of about 0.01 to about 5% w / v, about 0.1 to about 3% w / v, about 0.5 to about 2.5% w / v, or about 1 to about 2% w / v.

[0113] The daily dosage may be administered in a form that contains one or more oxathiazine-like compounds at a concentration of about 0.001 pg / ml to about 1000 pg / ml, about 0.01 pg / ml to about 750 pg / ml, about 0.05 pg / ml to about 500 pg / ml, about 0.1 pg / ml to about 300 pg / ml, about 0.5 pg / ml to about 200 pg / ml, about 1 pg / ml to about 100 pg / ml, about 5 pg / ml to about 50 pg / ml, about 10 pg / ml to about 25 pg / ml, or about 15 pg / ml to about 20 pg / ml. The daily dosage may be administered in a form that contains one or more solubilizing agents, e.g., polyols.

[0114] Effective dosage amounts of the oxathiazine-like compound are provided in a composition may include dosage units containing about 0.01-500 mg / kg, about 1-100 mg / kg per day, or about 5-50 mg / kg per day of the oxathiazine-like compound. In some aspects, dosageAttorney Docket No. 1194MS-540WO1 units are administered every other day, biweekly, or weekly.

[0115] The specific effective dose for any particular patient will depend on a variety of factors including the severity or likelihood of the neovascularization and / or excessive angiogenesis, disorder or disease; activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the preparation of the specific compound; the time and route of administration; the duration of administration; therapeutic agents used in combination or coinciding with the specific compound employed; and like factors known in the medical arts. The effective dose may also change over time as the C-MYC-mediated disorders, diseases, or conditions worsen or improve. For chronic conditions, subjects may receive effective doses for a plurality of days, weeks, months, years, or for the subject’s lifetime. The number of and frequency of administrations or co-administrations may vary depending upon the likelihood or severity of the C-MYC-mediated disorder, disease or condition, and the patient specific response to the particular compound administered and / or a second therapeutically active agent that is administered to the subject.

[0116] In another aspect, the present disclosure provides a method, kit, apparatus or device for providing a biomarker for clinical use. In some aspects, the present disclosure provides a biomarker for use in patients suffering from or at risk of suffering from cancer. In some aspects, the present disclosure provides a method of using C-MYC as a biomarker by obtaining a tumor tissue sample from a subject, and measuring C-MYC in the sample.

[0117] NUMBERED ITEMS

[0118] The present disclosure includes the following non-limiting items:1. A method of treating a subject having a c-Myc-mediated disease, disorder or condition comprising: a) obtaining a baseline biological sample from the subject and measuring a baseline level of c-Myc or c-Myc activity in the baseline biological sample;Attorney Docket No. 1194MS-540WO1 b) then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al,B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, c) then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of c-Myc or c-Myc activity in the post-treatment biological sample, d) and further comprising administering the compound to the subject if the posttreatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity. A method for identifying a candidate suitable for treatment with a c-MYC-inhibitor compound comprising: a) obtaining a baseline biological sample from the subject and measuring a baseline level of c-Myc or c-Myc activity in the baseline biological sample; b) then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, c) then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of c-Myc or c-Myc activity in the post-treatment biological sample, and d) identifying the subject as a suitable candidate for treating with the c-MYC- inhibitor compound if the post-treatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity. A method of treating a subject having a c-Myc-mediated disease, disorder or condition comprising:Attorney Docket No. 1194MS-540WO1 a) obtaining a biological sample from the subject and measuring a baseline level of c- Myc or c-Myc activity in the biological sample; b) then treating the biological sample in vitro with a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof, c) then measuring a post-treatment level of c-Myc or c-Myc activity in the biological sample, d) and further comprising administering the compound to the subject if the posttreatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity. A method for identifying a candidate suitable for treatment with a c-MYC-inhibitor compound comprising: a) obtaining a biological sample from the subject and measuring a baseline level of c-Myc or c-Myc activity in the biological sample; b) then treating the biological sample in vitro with a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof, c) then measuring a post-treatment level of c-Myc or c-Myc activity in the biological sample, and d) identifying the subject as a suitable candidate for treating with the c-MYC- inhibitor compound if the post-treatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity. A method for identifying a candidate suitable for treatment with a c-MYC-inhibitorAttorney Docket No. 1194MS-540WO1 compound comprising: a) obtaining a baseline biological sample from the subject and measuring a baseline level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity in the baseline biological sample; b) then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, c) then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity in the post-treatment biological sample, and d) identifying the subject as a suitable candidate for treating with the c-MYC- inhibitor compound if the post-treatment level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity is lower than the baseline level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB. A method for identifying a candidate suitable for treatment with a c-MYC-inhibitor compound comprising: a) obtaining a baseline biological sample from the subject and measuring a baseline level of ROS, pAMPK, pACC, pRaptor, or p53 in the baseline biological sample; b) then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject,Attorney Docket No. 1194MS-540WO1 c) then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of ROS, pAMPK, pACC, pRaptor, or p53 in the posttreatment biological sample, and d) identifying the subject as a suitable candidate for treating with the c-MYC- inhibitor compound if the post-treatment level of ROS, pAMPK, pACC, pRaptor, or p53 is higher than the baseline level of ROS, pAMPK, pACC, pRaptor, or p53. A method of treating a subject having a c-Myc-mediated disease, disorder or condition comprising: a) obtaining a baseline biological sample from the subject and measuring a baseline level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity in the baseline biological sample; b) then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, c) then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity in the post-treatment biological sample, d) and further comprising administering the compound to the subject if the posttreatment level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity is lower than the baseline level of Cyclin DI, Cyclin D2, Akt, mTOR, Bcl2, or NF-KB activity. A method of treating a subject having a c-Myc-mediated disease, disorder or condition comprising: a) obtaining a baseline biological sample from the subject and measuring a baseline level of ROS, pAMPK, pACC, pRaptor, or p53 in the baseline biological sample;Attorney Docket No. 1194MS-540WO1 b) then administering a compound selected from Formula I, 2250, 2245, 2256, Bl, Al, B2, A3, B3, 2261, 2264, 2244, 2289, 2293, 2296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, c) then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of ROS, pAMPK, pACC, pRaptor, or p53 in the post-treatment biological sample, d) and further comprising administering the compound to the subject if the posttreatment level of ROS, pAMPK, pACC, pRaptor, or p53 is lower than the baseline level of ROS, pAMPK, pACC, pRaptor, or p53. The method of any preceding item, wherein each biological sample is a tumor tissue sample. The method of any preceding items, wherein step b) and / or step d) comprises administering a dosage of 0.1-1000 mg / kg of the compound. The method of any preceding items, wherein step b) and / or step d) comprises administering a total daily dose of about 0.1 g to about 100 g of the compound. The method of any preceding items, wherein a dose of about 20 g to about 40 g of the compound is administered. The method of any preceding items, wherein 2250 is administered to the subject. The method of any preceding items, wherein the subject has suffered from or is suffering from a tumor, a cancer, a skin disease, a diabetic ulcer, a chronic wound, a cardiovascular disease, stroke, a traumatic brain injury, macular degeneration, impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, impaired autophagy, or a combination thereof.Attorney Docket No. 1194MS-540WO115. The method of any preceding items, wherein the composition is administered intravenously, subcutaneously, intramuscularly, topically, orally, intraperitoneally, intrathecally, intranasally, ophthalmically, intrapulmonary, transdermally, intraocularly, by inhalation, transtracheally, by intravitreal injection, or a combination thereof.16. The method of any preceding items, wherein the subject has pancreatic cancer.17. The method of any preceding items, wherein the subject has ovarian cancer.18. The method of any preceding items, wherein the subject has a platinum-resistant tumor.19. The method of any preceding items, wherein the subject has a neuroendocrine tumor.20. The method of any preceding items, wherein the subject has melanoma.21. The method of any preceding items, wherein the subject has a squamous cell carcinoma.22. The method of any preceding items, wherein the subject has a breast cancer tumor.23. The method of any preceding items, wherein the subject has a colon cancer tumor.24. The method of any preceding items, further comprising administering gemcitabine.

[0119] EXAMPLES

[0120] Aspects of the present disclosure will be further described with reference to the following Examples, which are provided for illustrative purposes only and should not be used to limit the scope of or construe the invention.

[0121] EXAMPLE 1

[0122] Inhibiting c-MYC Activity

[0123] An in vitro assay was performed to determine the effect of GP-2250 on c-MYC protein. Specifically, human recombinant c-MYC was incubated with GP-2250 for 30 minutes at increasing concentrations (0 pM, 250 pM, 500 pM, 750 pM, and 1000 pM). Activity of the recombinant c-MYC was assayed using c-Myc Transcription Factor Assay Kit (Abeam, ab207200), which provides a readout for c-MYC binding to DNA. Percent activity relative to untreated control decreased with increasing concentration of GP-2250 (FIG. 1). The results demonstrate that GP-2250 interacts directly with c-MYC and interferes with its ability to bind toAttorney Docket No. 1194MS-540WO1DNA.

[0124] A cellular assay was performed to determine the effects of GP-2250 on naturally occurring c-MYC. Specifically, pancreatic cancer cells from the cell line Pane Tul and pancreatic primary cells from the cell line Bo80 were incubated for 24 hours with increasing concentrations of GP-2250 (0 pM, 250 pM, 500 pM, 750 pM, and 1000 pM). Nuclear extracts were assayed using c-Myc Transcription Factor Assay Kit (Abeam, ab207200) to determine c- MYC activity. Percent activity relative to untreated control cells decreased with increasing concentration of GP-2250 (FIGs. 2A and 2B). These results demonstrate a dose-dependent reduction of c-MYC binding to DNA in both Pane Tul (FIG. 2A) and Bo80 (FIG. 2B) cells.

[0125] EXAMPLE 2

[0126] Reducing an Amount of c-MYC

[0127] An assay was performed to determine the effect of GP-2250 on the cellular concentration of c-MYC. Specifically, Pane Tul and Bo80 cells were incubated with GP-2250 at different times (6 h, 12 h, and 24 h) and concentrations (250 pM, 500 pM, and 1000 pM). Following incubation, cell lysate was analyzed by Western blot to measure the amount of c- MYC relative to untreated control cells. The results demonstrate that the amount of c-MYC in Pane Tul (FIGs. 3A and 3B) and Bo80 (FIGs. 4A and 4B) cells decreases with increasing concentration of GP-2250 and increasing time of incubation.

[0128] EXAMPLE 3

[0129] Generation of Reactive Oxygen Species and Inhibition of NF-KB

[0130] Cells from pancreatic cancer cell lines Pane Tul and BxPC3 were incubated with various concentrations of GP-2250 for 90 minutes. Generation of reactive oxygen species (ROS) was analyzed using the Cellular ROS / Superoxide Detection Assay Kit (abl39476,Abeam) following the manufacturer's instructions. In both Pane Tul (FIG. 5, panel A) and BxPC3 (FIG. 5, panel B) cells, a strong rise in ROS was apparent at increasing concentrations of GP-2250 compared to an untreated control (UC) and a negative control (NC) that was treatedAttorney Docket No. 1194MS-540WO1 with N-acetylcysteine (5 mM) in the presence of 1000 pM GP-2250.

[0131] The transcription factor NF-KB was assayed with the NFKB p65 Transcription Factor Assay Kit (Abeam, abl33112) following the manufacturer's instructions. Lysates were prepared either from drug-treated cells or, alternatively, from untreated cells with the lysates being directly incubated with GP-2250. The nuclear extracts were prepared with the Nuclear Extraction Kit (Abeam, abl 13474) according to the manufacturer's instructions. p65 / DNA binding was dose-dependently inhibited following incubation of Pane Tul (FIG. 5, panel C) and BxPC3 (FIG. 5, panel D) cells with GP-2250 (250-1000 pM) for 24 h, as tested in lysates of the nuclear fraction. Bay 117082 (10 pM) served as control. p65 / DNA binding in lysates of the nuclear fraction from untreated Pane Tul (FIG. 5, panel E) and BxPC3 (FIG. 5, panel F) cells incubated directly with GP-2250 (250, 500 and 1000 pM) was also dose-dependently inhibited.

[0132] EXAMPLE 4

[0133] Activation ofAMPK

[0134] Cells from pancreatic cancer cell lines Pane Tul and BxPC3 were incubated with various concentrations of GP-2250 for 6 hours, 12 hours, or 24 hours. Levels of phosphorylated AMPK (pAMPK) and Cyclin DI were determined by western blot (FIG. 6, panel A) and quantified (FIG. 6, panel B) relative to negative control (NC). In the presence of GP-2250, the phosphorylation of AMPK at Threonine 172 was increased in a time- and concentrationdependent manner. Additionally, the level of Cyclin DI was decreased in a time-dependent manner. [3-actin / HSP-9O were used as internal controls.

[0135] EXAMPLE 5

[0136] Phosphorylation of ACC and Raptor

[0137] Cells from pancreatic cancer cell lines Pane Tul and BxPC3 were incubated with 250 pM and 500 pM GP-2250, respectively, for 6 hours, 12 hours, or 24 hours. Levels of mTOR, phosphorylated ACC (pACC), phosphorylated Raptor (pRaptor), Akt, p53, and Bcl2 were determined by western blot (FIG. 7, panel A) and quantified (FIG. 7, panel B) relative toAttorney Docket No. 1194MS-540WO1 the 6 h incubation group. The results demonstrate a time-dependent decrease in the level of mTOR, Akt, and Bcl2 and a time-dependent increase in the level of pACC, pRaptor, and p53.

[0138] EXAMPLE 6

[0139] Measuring in vivo c-MYC or c-MYC Activity Levels in a Method of Treatment

[0140] A level of c-MYC or c-MYC activity may be used in a method of treating a subject having a c-MYC-mediated disease, disorder, or condition. Patients receiving an oxathiazine-like compound of the present disclosure may have a biological sample collected before and after being administered the compound. A level of c-MYC or c-MYC activity is then measured for both the baseline and post-treatment biological samples. If the post-treatment level is lower than the baseline level, the subject is administered an additional dose of the compound. The compound is administered at a dose of 0.1-1000 mg / kg, or at a total daily dose of about 0.1 to about 100 g, or at a dose of about 20 g to about 40 g.

[0141] EXAMPLE ?

[0142] Measuring in vivo c-MYC or c-MYC Activity Levels in a Method of Patient Selection

[0143] A level of c-MYC or c-MYC activity may be used in a method for identifying a candidate suitable for treatment with a c-MYC-inhibitor compound. A baseline biological sample is obtained from a subject, and then the subject is administered an oxathiazine-like compound of the present disclosure. Following administration, a post-treatment biological sample is obtained, and a level of c-MYC or c-MYC activity is then measured for both the baseline and post-treatment biological samples. If the post-treatment level is lower than the baseline level, the subject is identified as a suitable candidate for treating with the c-MYC- inhibitor compound. The compound is administered at a dose of 0.1-1000 mg / kg, or at a total daily dose of about 0.1 to about 100 g, or a dose of about 20 g to about 40 g.

[0144] EXAMPLE 8Attorney Docket No. 1194MS-540WO1

[0145] Measuring in vitro c-MYC or c-MYC Activity Levels in a Method of Treatment

[0146] A level of c-MYC or c-MYC activity may be used in a method of treating a subject having a c-MYC-mediated disease, disorder, or condition. Patients receiving an oxathiazine-like compound of the present disclosure may have a biological sample collected before being administered the compound. A baseline level of c-MYC or c-MYC activity is measured for the biological sample, the biological sample is treated with compound in vitro, and then a post-treatment level of c-MYC or c-MYC activity is measured for the biological sample. If the post-treatment level is lower than the baseline level, the subject is administered the compound at a dose of 0.1-1000 mg / kg, or at a total daily dose of about 0.1 to about 100 g, or at a dose of about 20 g to about 40 g.

[0147] EXAMPLE 9

[0148] Measuring in vitro c-MYC or c-MYC Activity Levels in a Method of Patient Selection

[0149] A level of c-MYC or c-MYC activity may be used in a method for identifying a candidate suitable for treatment with a c-MYC-inhibitor compound. A biological sample is obtained from a subject, and baseline level of c-MYC or c-MYC activity is measured for the biological sample. Then the biological sample is treated in vitro with 0.1-1000 mg / kg of an oxathiazine-like compound of the present disclosure. Following treatment, a post-treatment level of c-MYC or c-MYC activity is then measured. If the post-treatment level is lower than the baseline level, the subject is identified as a suitable candidate for treating with the c-MYC- inhibitor compound. The method may further comprise administering to the subject the compound at a dose of 0.1-1000 mg / kg, or at a total daily dose of about 0.1 to about 100 g, or at a dose of about 20 g to about 40 g.

[0150] EXAMPLE 10

[0151] Measuring expression of Cyclin D2Attorney Docket No. 1194MS-540WO1

[0152] Cells from pancreatic cancer cell line Pane Tul were incubated with various concentrations of GP-2250 (250 uM, 500 uM, 1000 uM) for 6 hours, 12 hours, or 24 hours. Levels of Cyclin D2 were determined by western blot and quantified (FIG. 8) relative to vinculin control (N). In the presence of GP-2250, the level of Cyclin D2 was decreased in a dose- and time-dependent manner.

[0153] While the subject matter of this disclosure has been described and shown in considerable detail with reference to certain illustrative examples, including various combinations and sub-combinations of features, those skilled in the art will readily appreciate other aspects and variations and modifications thereof as encompassed within the scope of the present disclosure. Moreover, the descriptions of such aspects, combinations, and subcombinations is not intended to convey that the claimed subject matter requires features or combinations of features other than those expressly recited in the claims. Accordingly, the scope of this disclosure is intended to include all modifications and variations encompassed within the spirit and scope of the following appended claims.

Claims

Attorney Docket No. 1194MS-540WO1CLAIMSWe claim:

1. A method of treating a subject having a c-Myc-mediated disease, disorder or condition comprising: a) obtaining a baseline biological sample from the subject and measuring a baseline level of c-Myc or c-Myc activity in the baseline biological sample; b) then administering a compound selected from Formula I[Formula I], wherein R is H, an in vivo cleavable linker or group, or a leaving group in aqueous solution and Ri and R2 are independently, H, alkyl, an aryl, a substituted alkyl, a substituted phenyl, a substituted aryl, or a combination thereof, or a compound selected from the group consisting of the following:Attorney Docket No. 1194MS-540WO1Attorney Docket No. 1194MS-540WO12296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, c) then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of c-Myc or c-Myc activity in the post-treatment biological sample, d) and further comprising administering the compound to the subject if the posttreatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity.

2. The method of claim 1 , wherein the baseline biological sample and the post-treatment biological sample are each a tumor tissue sample.

3. The method of any preceding claim, wherein step b) and / or step d) comprises administering a dosage of 0.1-1000 mg / kg of the compound.

4. The method of any preceding claims, wherein step b) and / or step d) comprises administering a total daily dose of about 0.1 g to about 100 g of the compound.

5. The method of any preceding claim, wherein step b) and / or step d) comprises administering a dose of about 20 g to about 40 g of the compound.

6. The method of any preceding claim, wherein 2250 is administered to the subject.Attorney Docket No. 1194MS-540WO17. The method of any preceding claim, wherein the subject has suffered from or is suffering from a tumor, a cancer, a skin disease, a diabetic ulcer, a chronic wound, a cardiovascular disease, stroke, a traumatic brain injury, macular degeneration, impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, impaired autophagy, or a combination thereof.

8. The method of any preceding claim, wherein the composition is administered intravenously, subcutaneously, intramuscularly, topically, orally, intraperitoneally, intrathecally, intranasally, ophthalmically, intrapulmonary, transdermally, intraocularly, by inhalation, transtracheally, by intravitreal injection, or a combination thereof.

9. A method for identifying a candidate suitable for treatment with a c-MYC-inhibitor compound comprising: a) obtaining a baseline biological sample from the subject and measuring a baseline level of c-Myc or c-Myc activity in the baseline biological sample; b) then administering a compound selected from Formula I[Formula I], wherein R is H, an in vivo cleavable linker or group, or a leaving group in aqueous solution and Ri and R2 are independently, H, alkyl, an aryl, a substituted alkyl, a substituted phenyl, a substituted aryl, or a combination thereof, or a compound selected from the group consisting of the following:Attorney Docket No. 1194MS-540WO1Attorney Docket No. 1194MS-540WO12296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof to the subject, c) then obtaining a post-treatment biological sample from the subject and measuring a post-treatment level of c-Myc or c-Myc activity in the post-treatment biological sample, and d) identifying the subject as a suitable candidate for treating with the c-MYC- inhibitor compound if the post-treatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity.

10. The method of claim 9, wherein the baseline biological sample and the post-treatment biological sample are each a tumor tissue sample.

11. The method of claim 9 or 10, wherein step b) comprises administering a dosage of 0.1- 1000 mg / kg of the compound.

12. The method of any one of claims 9-11, wherein step b) comprises administering a total daily dose of about 0.1 g to about 100 g of the compound.

13. The method of any one of claims 9-12, wherein step b) comprises administering a dose of about 20 g to about 40 g of the compound.

14. The method of any one of claims 9-13, wherein 2250 is administered to the subject.Attorney Docket No. 1194MS-540WO115. The method of any one of claims 9-14, wherein the subject has suffered from or is suffering from a tumor, a cancer, a skin disease, a diabetic ulcer, a chronic wound, a cardiovascular disease, stroke, a traumatic brain injury, macular degeneration, impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, an autoimmune disease, a immune reaction, excessive angiogenesis, dysfunctional apoptosis of normal cells, impaired autophagy, or a combination thereof.

16. The method of any one of claims 9-15, wherein the composition is administered intravenously, subcutaneously, intramuscularly, topically, orally, intraperitoneally, intrathecally, intranasally, ophthalmically, intrapulmonary, transdermally, intraocularly, by inhalation, transtracheally, by intravitreal injection, or a combination thereof.

17. A method of treating a subject having a c-Myc-mediated disease, disorder or condition comprising: a) obtaining a biological sample from the subject and measuring a baseline level of c- Myc or c-Myc activity in the biological sample; b) treating the biological sample in vitro with a compound selected from Formula I[Formula I], wherein R is H, an in vivo cleavable linker or group, or a leaving group in aqueous solution and Ri and R2 are independently, H, alkyl, an aryl, a substituted alkyl, a substituted phenyl, a substituted aryl, or a combination thereof, or a compound selected from the group consisting of the following:Attorney Docket No. 1194MS-540WO1Attorney Docket No. 1194MS-540WO12296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof, c) then measuring a post-treatment level of c-Myc or c-Myc activity in the biological sample, d) and further comprising administering the compound to the subject if the posttreatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity.

18. The method of claim 17, wherein the biological sample is a tumor tissue sample.

19. The method of claim 17 or 18, wherein step b) comprises treating the biological sample with 0.1-1000 mg / kg of the compound.

20. The method of any one of claims 17-19, wherein step d) comprises administering a total daily dose of about 0.1 g to about 100 g of the compound.

21. The method of any one of claims 17-20, wherein step d) comprises administering a dose of about 20 g to about 40 g of the compound.

22. The method of any one of claims 17-21, wherein 2250 is administered to the subject.

23. The method of any one of claims 17-22, wherein the subject has suffered from or is suffering from a tumor, a cancer, a skin disease, a diabetic ulcer, a chronic wound, aAttorney Docket No. 1194MS-540WO1 cardiovascular disease, stroke, a traumatic brain injury, macular degeneration, impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, impaired autophagy, or a combination thereof.

24. The method of any one of claims 17-23, wherein the composition is administered intravenously, subcutaneously, intramuscularly, topically, orally, intraperitoneally, intrathecally, intranasally, ophthalmically, intrapulmonary, transdermally, intraocularly, by inhalation, transtracheally, by intravitreal injection, or a combination thereof.

25. A method for identifying a candidate suitable for treatment with a c-MYC-inhibitor compound comprising: a) obtaining a biological sample from the subject and measuring a baseline level of c- Myc or c-Myc activity in the biological sample; b) treating the biological sample in vitro with a compound selected from Formula I[Formula I], wherein R is H, an in vivo cleavable linker or group, or a leaving group in aqueous solution and Ri and R2 are independently, H, alkyl, an aryl, a substituted alkyl, a substituted phenyl, a substituted aryl, or a combination thereof, or a compound selected from the group consisting of the following:Attorney Docket No. 1194MS-540WO1Attorney Docket No. 1194MS-540WO12296, a pharmaceutically acceptable salt, hydrate, ester, prodrug, or solvate thereof, or a combination thereof, c) then measuring a post-treatment level of c-Myc or c-Myc activity in the biological sample, and d) identifying the subject as a suitable candidate for treating with the c-MYC-inhibitor compound if the post-treatment level of c-Myc or c-Myc activity is lower than the baseline level of c-Myc or c-Myc activity.

26. The method of claim 25, wherein the biological sample is a tumor tissue sample.

27. The method of claim 25 or 26, wherein step b) comprises treating the biological sample with 0.1-1000 mg / kg of the compound.

28. The method of any one of claims 25-27, further comprising administering the compound to the subject.

29. The method of claim 28, comprising administering a dosage of 0.1-1000 mg / kg of the compound.

30. The method of claim 28 or claim 29, comprising administering a total daily dose of about0.1 g to about 100 g of the compound.Attorney Docket No. 1194MS-540WO131. The method of any one of claims 28-30, comprising administering a dose of about 20 g to about 40 g of the compound.

32. The method of any one of claims 25-31, wherein the compound is 2250.

33. The method of any one of claims 25-32, wherein the subject has suffered from or is suffering from a tumor, a cancer, a skin disease, a diabetic ulcer, a chronic wound, a cardiovascular disease, stroke, a traumatic brain injury, macular degeneration, impaired glycolysis, impaired protein degradation pathways, uncontrolled protein aggregation, aerobic glycolysis, mitochondrial dysfunction, increased glucose uptake or metabolism, neovascularization, autoimmune reactions, immune reactions, excessive angiogenesis, dysfunctional apoptosis of normal cells, impaired autophagy, or a combination thereof.

34. The method of any one of claims 28-33, wherein the composition is administered intravenously, subcutaneously, intramuscularly, topically, orally, intraperitoneally, intrathecally, intranasally, ophthalmically, intrapulmonary, transdermally, intraocularly, by inhalation, transtracheally, by intravitreal injection, or a combination thereof.

35. The method of any one of claims 1-34, wherein the subject has pancreatic cancer.

36. The method of any one of claims 1-34, wherein the subject has ovarian cancer.

37. The method of any one of claims 1-34, wherein the subject has a platinum-resistant tumor.

38. The method of any one of claims 1-34, wherein the subject has a neuroendocrine tumor.

39. The method of any one of claims 1-34, wherein the subject has melanoma.

40. The method of any one of claims 1-34, wherein the subject has a squamous cell carcinoma.

41. The method of any one of claims 1-34, wherein the subject has a breast cancer tumor.Attorney Docket No. 1194MS-540WO142. The method of any one of claims 1-34, wherein the subject has a colon cancer tumor.

43. The method of any one of claims 1-34, further comprising administering gemcitabine.

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