# US 11,026,930 B1 · Compounds that interact with the Ras superfamily for the treatment of cancers, inflammatory diseases, rasopathies, and fibrotic disease

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- Number: US 11,026,930 B1
- Document ID: US11026930B1
- Status: Granted
- Kind: B1
- Application number: 16/847,467
- Filed: 2020-04-13
- Granted: 2021-06-08
- Earliest claimed: 2017-06-21
- Assignees: SHY Therapeutics LLC
- Applicants: Shy Therapeutics LLC
- Inventors: Yaron R. Hadari; Luca Carta; Michael Schmertzler; Theresa M. Williams; Charles H. Reynolds; Rebecca Hutcheson
- Web page: https://patentgrep.com/patent/US11026930B1

## CPC

- A61K 31/4365: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07D 495/04: Ortho-condensed systems
- C07K 14/435: from animals; from humans
- C12N 15/1037: {Screening libraries presented on the surface of microorganisms, e.g. phage display, E. coli display}
- C12N 15/1065: {Preparation or screening of tagged libraries, e.g. tagged microorganisms by STM-mutagenesis, tagged polynucleotides, gene tags}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Provided herein are methods and compositions for treating cancers, inflammatory diseases, rasopathies, and fibrotic disease involving aberrant Ras superfamily signaling through the binding of compounds to the GTP binding domain of Ras superfamily proteins including, in certain cases, K-Ras and mutants thereof, and a novel method for assaying such compositions.

## Claims

### Claim 1

An assay for identifying a compound as a modulator of Ras activity, wherein the assay comprises:
a) contacting a compound with a Ras protein;
b) incubating a cyanine-labeled GTP with the compound and the Ras protein; and
c) measuring the amount of the cyanine-labeled GTP bound to the Ras protein.

### Claim 2 (depends on 1)

The assay of claim 1, wherein the assay is a cell-free assay.

### Claim 3 (depends on 1)

The assay of claim 1, wherein the Ras protein is DIRAS I; DIRAS2; DIRAS3; ERAS; GEM; HRAS; KRAS; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAPIA; RAPIB; RAP2 Å; RAP2B; RAP2C; RASD1; RASD2; RASLIOA; RASL10B; RASLI IA; RASLI IB; RASL12; REMI; REM2; RERG; RERGL; RRAD; RRAS; or RRAS2.

### Claim 4 (depends on 1)

The assay of claim 1, wherein the Ras protein is HRAS; KRAS; or NRAS, or a mutant thereof.

### Claim 5 (depends on 1)

The assay of claim 1, wherein the Ras protein is immobilized.

### Claim 6 (depends on 1)

The assay of claim 1, wherein the compound competitively inhibits GTP binding to the Ras GTP binding domain.

### Claim 7 (depends on 1)

The assay of claim 1, wherein the compound binds to the Ras protein GTP binding domain with greater than 25% inhibition at 20 uM.

### Claim 8 (depends on 1)

The assay of claim 1, wherein the compound has a binding affinity (Kd) to the Ras protein GTP binding domain of less than 10 uM.

### Claim 9 (depends on 1)

The assay of claim 1, wherein the compound inhibits the Ras activity and has an IC50 value of less than 10 uM.

### Claim 10 (depends on 1)

The assay of claim 1, wherein the compound inhibits binding of the cyanine-labeled GTP with an IC50 value of less than 10 uM.

### Claim 11 (depends on 1)

The assay of claim 1, wherein the cyanine-labeled GTP is a Cy3- or a Cy5-labeled GTP.

### Claim 12 (depends on 1)

The assay of claim 1, wherein the assay is a GTP-binding competition assay.

### Claim 13 (depends on 1)

The assay of claim 1, wherein the Ras protein is a KRas G12D mutant, KRas G12C mutant, or KRas Q61H mutant.

### Claim 14 (depends on 1)

The assay of claim 1, wherein the Ras protein is wild-type KRas.

### Claim 15 (depends on 1)

The assay of claim 1, wherein the compound has a molecular weight of less than 2000 Daltons.

### Claim 16 (depends on 1)

The assay of claim 1, wherein the compound has a molecular weight of less than 750 Daltons.