# US 2023/0068698 A1 · Combination therapy for cancer

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- Number: US 2023/0068698 A1
- Document ID: US20230068698A1
- Status: Published application
- Kind: A1
- Application number: 17/792,387
- Filed: 2021-01-13
- Published: 2023-03-02
- Earliest claimed: 2020-01-14
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Michael Karin; Hua Su
- Web page: https://patentgrep.com/patent/US20230068698A1

## CPC

- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- 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 are methods and compositions for treating cancer through a combination of an inhibitor of macropinocytosis upregulation and an autophagy inhibitor. Also provided are methods and compositions for inducing cell death of cancer cells, and transgenic animal models regarding same.

## Claims

### Claim 1

A method of inducing cell death of a cancer cell, the method comprising, contacting the cancer cell with:
(1) an inhibitor of macropinocytosis upregulation, wherein the inhibitor of macropinocytosis upregulation is selected from 5-(N-ethyl-N-isopropyl) amiloride (EIPA), 3-methylsulphonyl-4-piperidinobenzoyl)guanidine methanesulphonate (HOE-694), amiloride and amiloride derivatives, eganelisib, IPI-549, MBO-167, wortmannin, LP1-106, XRK3F2, ML385, Brusatol, LY294002, a sodium-proton exchanger inhibitor, a sodium-calcium exchanger inhibitor, a sodium channel inhibitor, an inhibitor of activity or expression of one or more proteins selected from NRF2, PIK3CG, PAK1, SLC9A1, SNX5, SDC1, NHE1, p110α, p110γ, p62, CDC42, EGFR, EGF, or a combination thereof; and
(2) an autophagy inhibitor, wherein the autophagy inhibitor is selected from 3-Methyladenine (3-MA), LY294002, Bafilomycin A1 (Baf A1), Chloroquine (CO), hydroxychloroquine (HCO), ABT-737, an IKKα downregulator, obatoclax, Clarithromycin, Resveratrol, Quinacrine, 4-Acetylantroquinonol B, antroquinonol, Epigallocatechin gallate (EGCG), MRT68921 dihydrochloride, ULK1 inhibitors, MRT67307, SBI-0206965, ULK-100, ULK-101, DCC-3116, SAR405, Vps34-IN1 (PIK-III), SU1261, Vps34 inhibitors, or a combination thereof,
thereby inducing cell death of the cancer cell.

### Claim 2 (depends on 1)

The method of claim 1, wherein the cancer cell is breast cancer, triple negative breast cancer, non-small-cell lung cancer, pancreatic cancer, leukemia, melanoma, colorectal cancer, bladder cancer, lung cancer, or pancreatic ductal adenocarcinoma (PDAC) cell.

### Claim at position 3

3-5. (canceled)

### Claim 6 (depends on 1)

The method of claim 1, wherein the autophagy inhibitor is an inhibitor of ULK1, MRT68921 dihydrochloride, ULK-100, ULK-101, DCC-3116, or SBI-0206965.

### Claim at position 5

7-9. (canceled)

### Claim 10 (depends on 1)

The method of claim 1, wherein the autophagy inhibitor is an IKKα downregulator.

### Claim 11

(canceled)

### Claim 12 (depends on 1)

The method of claim 1, wherein the inhibitor of macropinocytosis upregulation is:
(a) an inhibitor of activity or expression of NRF2 or 62; or
(b) 5-(N-ethyl-N-isopropyl), 5-(N-ethyl-N-isopropyl) amiloride 3-methylsulphonyl-4-piperidinobenzoyl) guanidine methanesulphonate, or IPI-549.

### Claim at position 9

13-15. (canceled)

### Claim 16 (depends on 12)

The method of claim 12, wherein the inhibitor of;
(a) NRF2 activity or expression is ML385 or Brusatol; or
(b) p62 activity or expression is LP1-106 or XRK3F2.

### Claim at position 11

17-19. (canceled)

### Claim 20 (depends on 1)

The method of claim 1, wherein the contacting the cancer cell with the inhibitor of macropinocytosis upregulation and the autophagy inhibitor is sequential or concurrent.

### Claim 21

A method of treating cancer in a subject in need thereof, the method comprising administering to the subject;
(a) an inhibitor of macropinocytosis upregulation, wherein the inhibitor of macropinocytosis upregulation is selected from 5-(N-ethyl-N-isopropyl) amiloride (EIPA), 3-methylsulphonyl-4-piperidinobenzoyl)guanidine methanesulphonate (HOE-694), amiloride and amiloride derivatives, eganelisib, IPI-549, MBO-167, wortmannin, LP1-106, XRK3F2, ML385, Brusatol, LY294002, a sodium-proton exchanger inhibitor, a sodium-calcium exchanger inhibitor, a sodium channel inhibitor, an inhibitor of activity or expression of one or more proteins selected from NRF2, PIK3CG, PAK1, SLC9A1, SNX5, SDC1, NHE1, p110α, p110γ, p62, CDC42, EGFR, EGF, or a combination thereof; and
(b) an autophagy inhibitor, wherein the autophagy inhibitor is selected from 3-Methyladenine (3-MA), LY294002, Bafilomycin A1 (Baf A1), Chloroquine (CQ), hydroxychloroquine (HCQ), ABT-737, obatoclax, Clarithromycin, Resveratrol, Quinacrine, 4-Acetylantroquinonol B, antroquinonol, Epigallocatechin gallate (EGCG), MRT68921 dihydrochloride, ULK1 inhibitors, an IKKα downregulator, MRT67307, SBI-0206965, ULK-100, ULK-101, DCC-3116, SAR405, Vps34-IN1 (PIK-III), SU1261, Vps34 inhibitors, or a combination thereof,
thereby treating cancer in the subject.

### Claim 22 (depends on 21)

The method of claim 21, wherein the cancer is breast cancer, triple negative breast cancer, non-small-cell lung cancer, pancreatic cancer, leukemia, melanoma, colorectal cancer, bladder cancer, lung cancer or pancreatic ductal adenocarcinoma (PDAC).

### Claim at position 15

23-24. (canceled)

### Claim 25 (depends on 21)

The method of claim 21, wherein the autophagy inhibitor is an inhibitor of ULK1, MRT68921 dihydrochloride, ULK-100, ULK-101, DCC-3116, or SBI-0206965.

### Claim at position 17

26-28. (canceled)

### Claim 29 (depends on 21)

The method of claim 21, wherein the autophagy inhibitor is an IKKα downregulator.

### Claim at position 19

30-33. (canceled)

### Claim 34 (depends on 21)

The method of claim 21, wherein the inhibitor of macropinocytosis upregulation is:
(a) an inhibitor of activity or expression of NRF2 or 62; or
(b) 5-(N-ethyl-N-isopropyl), 5-(N-ethyl-N-isopropyl) amiloride 3-methylsulphonyl-4-piperidinobenzoyl) guanidine methanesulphonate, or IPI-549.

### Claim 35 (depends on 34)

The method of claim 34, wherein the inhibitor of;
(a) NRF2 activity or expression is ML385 or Brusatol; or
(b) p62 activity or expression is LP1-106 or XRK3F2.

### Claim at position 22

36-37. (canceled)

### Claim 38 (depends on 21)

The method of claim 21, wherein the inhibitor of macropinocytosis upregulation and the autophagy inhibitor are administered sequentially or concurrently.

### Claim 39

A composition for inducing cancer cell death comprising an inhibitor of macropinocytosis upregulation and an autophagy inhibitor, wherein:
(a) the inhibitor of macropinocytosis upregulation is selected from 5-(N-ethyl-N-isopropyl)amiloride (EIPA), 3-methylsulphonyl-4-piperidinobenzoyl)guanidine methanesulphonate (HOE-694), amiloride and amiloride derivatives, eganelisib, IPI-549, MBQ-167, wortmannin, LP1-106, XRK3F2, LY294002, an inhibitor of activity or expression of one or more proteins of NRF2, PIK3CG, PAK1, SLC9A1, SNX5, SDC1, NHE1, p110α, p110γ, p62, CDC42, EGFR, EGF, ML385, brusatol, or a combination thereof; and
(b) the autophagy inhibitor is selected from the group consisting of 3-Methyladenine (3-MA), LY294002, bafilomycin A1 (Baf A1), chloroquine (CQ), hydroxychloroquine (HCQ), ABT-737, obatoclax, clarithromycin, resveratrol, ruinacrine, 4-acetylantroquinonol B, antroquinonol, epigallocatechin gallate (EGCG), MRT68921 dihydrochloride, ULK1 inhibitors, an IKKα downregulator, MRT67307, SBI-0206965, ULK-100, ULK-101, DCC-3116, SAR405, Vps34-IN1 (PIK-III), SU1261, Vps34 inhibitors, or a combination thereof.

### Claim 40

(canceled)

### Claim 41 (depends on 39)

The composition of claim 39, wherein the cancer cell is breast cancer, triple negative breast cancer, non-small-cell lung cancer, pancreatic cancer, leukemia, melanoma, colorectal cancer, bladder cancer, lung cancer, or pancreatic ductal adenocarcinoma (PDAC) cell.

### Claim at position 27

42-43. (canceled)

### Claim 44 (depends on 39)

The composition of claim 39, wherein the autophagy inhibitor is an inhibitor of ULK1, MRT68921 dihydrochloride, ULK-100, ULK-101, DCC-3116, or SBI-0206965.

### Claim at position 29

45-47. (canceled)

### Claim 48 (depends on 39)

The composition of claim 39, wherein the autophagy inhibitor is an IKKα downregulator.

### Claim 49

(canceled)

### Claim 50 (depends on 39)

The composition of claim 39, wherein the inhibitor of macropinocytosis upregulation is:
(a) an inhibitor of activity or expression of NRF2 or 62; or
(b) 5-(N-ethyl-N-isopropyl), 5-(N-ethyl-N-isopropyl) amiloride 3-methylsulphonyl-4-piperidinobenzoyl) guanidine methanesulphonate, or IPI-549.

### Claim at position 33

51-53. (canceled)

### Claim 54 (depends on 50)

The composition of claim 50, wherein the inhibitor of:
(a) NRF2 activity or expression is ML385 or Brusatol; or
(b) p62 activity or expression is LP1-106 or XRK3F2.

### Claim at position 35

55-58. (canceled)