# US 11,998,534 B2 · GPX4 inhibitor in combination with anticancer agent for treating proliferative disease

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- Number: US 11,998,534 B2
- Document ID: US11998534B2
- Status: Granted
- Kind: B2
- Application number: 17/173,416
- Filed: 2021-02-11
- Published: 2021-08-12
- Granted: 2024-06-04
- Earliest claimed: 2020-02-12
- Assignees: Eubulus Biotherapeutics Inc.
- Applicants: Eubulus Biotherapeutics Inc.
- Inventors: Sheldon Cao
- Web page: https://patentgrep.com/patent/US11998534B2

## CPC

- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/245: Amino benzoic acid types, e.g. procaine, novocaine (salicylic acid esters A61K31/60)
- A61K 31/265: of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- 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

## Abstract

Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a GPX4-mediated disorder, disease, or condition in a subject with a GPX4 inhibitor and an anticancer agent. Also provided herein are methods of inducing ferroptosis in a cell or inhibiting the growth of a cell with a GPX4 inhibitor and an anticancer agent.

## Claims

### Claim 1

A method of abrogating or alleviating cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a glutathione peroxidase 4 inhibitor and a therapeutically effective amount or a subtherapeutically effective amount of an anticancer agent; wherein the cancer is colorectal adenocarcinoma, hepatocellular carcinoma, or ovarian adenocarcinoma; wherein the glutathione peroxidase 4 inhibitor is methyl 4-((3R)-3-(hydroxymethyl)-2-propioloyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)benzoate or N-(1-(4-aminophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(3-chloro-4-methoxyphenyl)-propiolamide; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein the anticancer agent is neratinib, regorafenib, or sorafenib.

### Claim 2 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of the anticancer agent is ranging from about 0.1 to about 100 mg/kg/day or from about 1 to about 2,000 mg per day.

### Claim 3 (depends on 1)

The method of claim 1, wherein the cancer is metastatic, refractory, and/or relapsed.

### Claim 4 (depends on 1)

The method of claim 1, wherein the cancer is drug resistant or multidrug-resistant.

### Claim 5 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of the glutathione peroxidase 4 inhibitor is ranging from about 0.01 to about 100 mg/kg/day or from about 1 to about 1,000 mg per day.

### Claim 6 (depends on 1)

The method of claim 1, wherein the glutathione peroxidase 4 inhibitor is administered orally.

### Claim 7 (depends on 1)

The method of claim 1, wherein the anticancer agent is neratinib.

### Claim 8 (depends on 1)

The method of claim 1, wherein the anticancer agent is administered orally.

### Claim 9 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 10

A method of inhibiting the growth of a cancerous cell or inducing ferroptosis in a cancerous cell, comprising contacting the cell with an effective amount of a GPX4 inhibitor and an effective amount or a subeffective amount of an anticancer agent; wherein the glutathione peroxidase 4 inhibitor is methyl 4-((3R)-3-(hydroxymethyl)-2-propioloyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)benzoate or N-(1-(4-aminophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(3-chloro-4-methoxyphenyl)-propiolamide; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein the anticancer agent is neratinib, regorafenib, or sorafenib.

### Claim 11 (depends on 1)

The method of claim 1, wherein the glutathione peroxidase 4 inhibitor is methyl 4-((3R)-3-(hydroxymethyl)-2-propioloyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)benzoate; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the glutathione peroxidase 4 inhibitor is N-(1-(4-aminophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(3-chloro-4-methoxyphenyl)-propiolamide; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein the anticancer agent is regorafenib.

### Claim 14 (depends on 1)

The method of claim 1, wherein the anticancer agent is sorafenib.

### Claim 15 (depends on 10)

The method of claim 10, wherein the glutathione peroxidase 4 inhibitor is methyl 4-((3R)-3-(hydroxymethyl)-2-propioloyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)benzoate; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

### Claim 16 (depends on 10)

The method of claim 10, wherein the glutathione peroxidase 4 inhibitor is N-(1-(4-aminophenyl)-2-(tert-butylamino)-2-oxoethyl)-N-(3-chloro-4-methoxyphenyl)-propiolamide; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

### Claim 17 (depends on 1)

The method of claim 1, wherein the subtherapeutically effective amount of the anticancer agent is no greater than about 0.5 of the therapeutically effective amount of the anticancer agent when administered alone as monotherapy.