# US 11,077,078 B2 · Compositions and methods for the treatment of cancer

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- Number: US 11,077,078 B2
- Document ID: US11077078B2
- Status: Granted
- Kind: B2
- Application number: 16/709,805
- Filed: 2019-12-10
- Published: 2020-09-03
- Granted: 2021-08-03
- Earliest claimed: 2006-02-16
- Assignees: Kodiscovery, LLC
- Applicants: KoDiscovery, LLC
- Inventors: Young Hee Ko
- Web page: https://patentgrep.com/patent/US11077078B2

## CPC

- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 8/97: from algae, fungi, lichens or plants; from derivatives thereof
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/202: having three or more double bonds, e.g. linolenic (eicosanoids, e.g. leukotrienes A61K31/557)
- A61K 31/33: Heterocyclic compounds
- A61K 31/375: Ascorbic acid, i.e. vitamin C; Salts thereof
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/43: Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula [IMAGE cpc-sch-A61K-0952.gif], e.g. penicillins, penems
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/70: Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K31/047)
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 31/7076: containing purines, e.g. adenosine, adenylic acid
- A61K 38/005: {Enzyme inhibitors (protease inhibitors A61K38/55)}
- A61K 38/44: Oxidoreductases (1)
- A61K 38/45: Transferases (2)
- A61K 45/00: Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C12Y 207/01001: Hexokinase (2.7.1.1)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Y: ENZYMES

## Abstract

The present invention discloses anti-cancer compositions, and associated methods, including an anti-cancer composition comprising: a cellular energy inhibitor having the structure according to formula I wherein X is selected from the group consisting of: a nitro, an imidazole, a halide, sulfonate, a carboxylate, an alkoxide, and amine oxide; and R is selected from the group consisting of: OR′, N(R″)2, C(O)R′″, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, a C6-C12 heteroaryl, H, and an alkali metal; where R′ represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R′″, R″ represents H, C1-C6 alkyl, or C6-C12 aryl, and R′″ represents H, C1-C20 alkyl or C6-C12 aryl. The anti-cancer composition can additionally comprise at least one sugar, which stabilizes the cellular energy inhibitor by substantially preventing the inhibitor from hydrolyzing. Also, the anti-cancer composition can comprise a hexokinase inhibitor. Further, the anti-cancer composition can comprise a biological buffer that is present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic by-products of the cellular energy inhibitor.

## Claims

### Claim 1

An anti-cancer composition comprising:
a) a cellular energy inhibitor having the structure according to formula I
wherein X is selected from the group consisting of: a nitro, an imidazole, a halide, sulfonate, a carboxylate, an alkoxide, and amine oxide; and R is selected from the group consisting of: OR′, N(R″)2, C(O)R′″, C1-C6 alkyl, C6-C12 aryl, C1-C6 heteroalkyl, a C6-C12 heteroaryl, H, and an alkali metal; where R′ represents H, alkali metal, C1-C6 alkyl, C6-C12 aryl or C(O)R′″, R″ represents H, C1-C6 alkyl, or C6-C12 aryl, and R′″ represents H, C1-C20 alkyl or C6-C12 aryl;
b) at least one sugar, which stabilizes the cellular energy inhibitor by substantially inhibiting the inhibitor from hydrolyzing;
c) a biological buffer that is present in an amount sufficient to at least partially deacidify the cellular energy inhibitor and neutralize metabolic by-products of the cellular energy inhibitor;
d) a hexokinase inhibitor; and
e) a glycolysis inhibitor;
wherein the anti-cancer composition treats a cancerous tumor that is positron emission tomography (PET) positive.

### Claim 2 (depends on 1)

The anti-cancer composition of claim 1, wherein the hexokinase inhibitor inhibits binding of hexokinase 1 and/or hexokinase 2 to voltage dependent anion channels VDAC.

### Claim 3 (depends on 1)

The anti-cancer composition of claim 1, wherein the hexokinase inhibitor is an amino acid sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO. 10.

### Claim 4 (depends on 1)

The anti-cancer composition of claim 1, further comprising at least one additive selected from the group consisting of: phospholipids; liposomes; nanoparticles; immune system modulators and/or immune system boosters including brown rice extract, muramyl dipeptide including analogues, mushroom extract, bioflavonoids, Vitamin D3-Binding Protein-Derived Macrophage Activating Factor (GcMAF), inhibitors of nagalase, threonine attached to N-acetylgalactosamine, and antibodies against nagalase; L-lactate dehydrogenase; D-lactate dehydrogenase; nicotinamide adenine dinucleotides; inhibitors for DNA replication; inhibitors for DNA binding; inhibitors for DNA transcription; inhibitors for cell cycle, growth and/or proliferation; inhibitors for signal transduction pathways; inhibitors for angiogensis; small RNAs that interfere with normal gene control including antisense RNA, micro RNA, small hairpin RNA, short hairpin RNA, small interfering RNA; vitamin C; nutritional supplements including vitamins, CoQ10, flavonoids, free fatty acid, alpha lipoic acid, acai, gogi, mango, pomergrante, L-carnitine, selenium; a less biologically active amino acid as compared to its isomer; and mixtures thereof.

### Claim 5 (depends on 1)

The anti-cancer composition of claim 1, wherein the cellular energy inhibitor is a 3-halopyruvate selected from the group consisting of: 3-fluoropyruvate, 3-chloropyruvate, 3-bromopyruvate, 3-iodopyruvate, and combinations thereof, in a concentration from about 1.0 mM to about 10.0 mM.

### Claim 6 (depends on 1)

The anti-cancer composition of claim 1, wherein the composition comprises a second sugar and a third sugar independently selected from the group consisting of mannitol, erytritol, isomalt, lactitol, maltitol, sorbitol, xyolitol, dulcitol, ribitol, inositol, sorbitol, and combinations thereof.

### Claim 7 (depends on 5)

The anti-cancer composition of claim 5, wherein the sugars are glycerol, inositol, and sorbitol and wherein the composition comprises glycerol in a range from about 0.1 wt % to about 3 wt %, inositol in a range from about 1 wt % to about 5 wt %, and sorbitol in a range from about 30 wt % to about 50 wt %.

### Claim 8 (depends on 1)

The anti-cancer composition of claim 1, further comprising d-lactic acid and epinephrine.

### Claim 9 (depends on 1)

The anti-cancer composition of claim 1, wherein the glycolysis inhibitor is 2-deoxglucose.

### Claim 10 (depends on 9)

The anti-cancer composition of claim 9, wherein the glycolysis inhibitor is in a concentration from about 1 mM to about 5 mM.

### Claim 11 (depends on 1)

The anti-cancer composition of claim 1, wherein the biological buffer is selected from the group consisting of a citrate buffer, a phosphate buffer, and an acetate buffer.

### Claim 12 (depends on 1)

The anti-cancer composition of claim 1, wherein the biological buffer is a citrate buffer.

### Claim 13 (depends on 1)

The anti-cancer composition of claim 1, wherein the by-product is a hydrogen halide and the biological buffer is sodium citrate.

### Claim 14 (depends on 13)

The anti-cancer composition of claim 13, wherein the hydrogen halide is hydrogen bromide.

### Claim 15 (depends on 1)

The anti-cancer composition of claim 1, wherein the biological buffer maintains a physiological pH of 5.5 to 8.0.

### Claim 16 (depends on 1)

The anti-cancer composition of claim 1, further comprising a halo monocarboxylate compound.

### Claim 17 (depends on 16)

The anti-cancer composition of claim 16, wherein the halo monocarboxylate compound is 2-bromoacetate in a concentration from about 0.1 mM to about 0.5 mM.

### Claim 18 (depends on 1)

The anti-cancer composition of claim 1, further comprising an antifungal agent, an antibacterial agent, or both in a concentration from about 0.05 mM to about 0.5 mM.

### Claim 19 (depends on 1)

The anti-cancer composition of claim 1, further comprising a mitochondrial inhibitor.

### Claim 20 (depends on 19)

The anti-cancer composition of claim 19, wherein the mitochondrial inhibitor is selected from the group consisting of: oligomycin, efrapeptin, aurovertin, and mixtures thereof; in a concentration from about 0.01 mM to about 0.5 mM.

### Claim 21 (depends on 1)

A method for the treatment of cancer, comprising administering to a subject the anti-cancer composition of claim 1 in a therapeutically effective amount.

### Claim 22 (depends on 21)

The method of claim 21, wherein the cancer is selected from the group consisting of: childhood fibrolamellar hepatocellular carcinoma (FHCC), hepatocellular carcinoma (HCC), lung cancer including non-small cell lung cancer, colon cancer, pancreatic cancer, liver cancer, breast cancer, cervical cancer, medulloblastoma, neuroblastoma, ovarian cancer, prostate cancer, skin cancer, and combinations thereof.