# US 11,433,068 B2 · Treatment of cancers having alterations within the SWI/SNF chromatin remodeling complex

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- Number: US 11,433,068 B2
- Document ID: US11433068B2
- Status: Granted
- Kind: B2
- Application number: 16/331,602
- Filed: 2017-09-07
- Published: 2019-07-04
- Granted: 2022-09-06
- Earliest claimed: 2016-09-08
- Assignees: The General Hospital Corporation
- Applicants: The General Hospital Corporation
- Inventors: David E. Fisher; Qing Yu Weng; Shinichiro Kato
- Web page: https://patentgrep.com/patent/US11433068B2

## CPC

- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/277: having a ring, e.g. verapamil
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/4995: Pyrazines or piperazines forming part of bridged ring systems
- A61K 31/542: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 31/711: Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
- A61P 35/00: Antineoplastic agents
- C12Q 1/6827: for detection of mutation or polymorphism
- 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
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

This disclosure provides compositions and methods of treating cancer by inhibiting histone methyltransferases alone or in combination by synergistically inhibiting a histone demethylase, or a histone deacetylase (HDAC), or a bromodomain (BRD)-containing protein, or a B-Raf kinase. In particular, the cancers have deficient of SWI/SNF chromatin remodeling complexes because of mutations in one or more of the complex's subunit members.

## Claims

### Claim 1

A method for treating melanoma in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a small molecule inhibitor of a histone methyltransferase, wherein the histone methyltransferase comprises G9a or GLP, and wherein the melanoma cells of the subject have been determined to have an alteration in the SWI/SNF ((SWItch/Sucrose Non-Fermentable) chromatin remodeling complex,
wherein the small molecule inhibitor is selected from the group consisting of BIX-01294, UNC0638, A-366, chaetocin, UNCO224, UNC0631, UNC0642, and UNC0646.

### Claim 2 (depends on 1)

The method of claim 1, wherein the alteration of the SWI/SNF chromatin remodeling complex is the result in a deficiency in one or more of the subunit member of the complex.

### Claim 3 (depends on 2)

The method of claim 2, wherein the subunits are selected from the group consisting of BRM/SMARCA2, BRG1/SMARCA4, ARID1A; ARID2; SMARCR2; SMARCR1; and SMARCB1.

### Claim 4 (depends on 3)

The method of claim 3, wherein the deficiency is due to a mutation in the gene of the subunit member, wherein the mutation is a deletion, a single nucleotide variant (SNV), an inactivating SNV, or an amplification.

### Claim 5 (depends on 1)

The method of claim 1, wherein the small molecule inhibitor is administered by a route selected from the group consisting of intravenous, intramuscular, subcutaneous, intradermal, topical, intraperitoneal, intrathecal, intrapleural, intrauterine, rectal, vaginal, intrasynovial, intraocular/periocular, intratumor, and parenteral administration.

### Claim 6 (depends on 1)

The method of claim 1, wherein the small molecule inhibitor is administered in conjunction with at least one additional cancer therapy to achieve a combination cancer therapy.

### Claim 7 (depends on 6)

The method of claim 6, wherein the at least one additional cancer therapy is selected from chemotherapy, radiation therapy, immunotherapy, surgery, hormone therapy, stem cell therapy, targeted therapy, gene therapy and precision therapy.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 8)

The method of claim 8, wherein the mammal is a human.

### Claim 10 (depends on 1)

The method of claim 1, wherein the small molecule inhibitor further comprises a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

The method of claim 1, wherein the melanoma cells have been further determined to have at least one of:
a. H3K9me2 levels at least 3-fold higher as compared to a reference level of H3K9me2 levels in a reference sample, or
b. at least 1 additional copy of the G9a and/or GLP gene as compared to a reference gene copy number of the G9a and/or GLP gene in the reference sample;
wherein the reference sample is a non-melanoma cell from the subject.