Methods and compositions related to retinoid receptor-selective pathway

Patent metadata

Field	Value
Publication number	US-10087156-B2
Application number	US-201715435125-A
Country	US
Kind code	B2
Filing date	Feb 16, 2017
Priority date	May 6, 2010
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

Provided herein are methods and compositions related to a retinoid receptor-selective pathway. As described herein, this pathway can be targeted to manipulate a tumor microenviroment. For example, the methods and compositions described herein can be used to induce apoptosis in a cancer cell. Further, the compositions described herein, including Sulindac and analogs thereof, can be used to target this pathway for the treatment or prevention of cancer in human patients.

First claim

What is claimed is:

1. A method of treating cancer in a patient in need thereof, wherein the method comprises administering to the patient a composition comprising a compound of formula (I), or a sodium salt thereof, wherein the compound of formula (I) has the following structure:

wherein A is a phenyl, and wherein A is substituted by one or two substituents independently selected from the group consisting of C2-3 alkyl, n-butyl, iso-butyl, sec-butyl, —CF 3 , a C3-C4 cycloalkyl, and a C4-C5 cycloalkylalkyl;
wherein B is a fused phenyl, and wherein B is substituted by a fluoro;
wherein R 1 is —(CR 5 R 6 ) n COOH;
wherein R 2 is CH 3 ;
wherein R 5 and R 6 are H; and
wherein n is 1 or 2.

2. A method of treating cancer in a patient in need thereof, wherein the method comprises systemically exposing the patient to a compound of formula (I) wherein the compound of formula (I) has the following structure:

wherein A is a phenyl, and wherein A is substituted by one or two substituents independently selected from the group consisting of C2-3 alkyl, n-butyl, iso-butyl, sec-butyl, —CF 3 , a C3-C4 cycloalkyl, and a C4-C5 cycloalkylalkyl;
wherein B is a fused phenyl, and wherein B is substituted by a fluoro;
wherein R 1 is —(CR 5 R 6 ) n COOH;
wherein R 2 is CH 3 ;
wherein R 5 and R 6 are H; and
n is 1 or 2; and
wherein the systemic exposure is by oral administration.

3. A method of treating cancer in a patient in need thereof, wherein the method comprises systemically exposing to the patient a compound of formula (I) wherein the compound of formula (I) has the following structure:

wherein A is a phenyl, and wherein A is substituted by one or two substituents independently selected from the group consisting of C2-3 alkyl, n-butyl, iso-butyl, sec-butyl, —CF 3 , a C3-C4 cycloalkyl, and a C4-C5 cycloalkylalkyl;
wherein B is a fused phenyl, and wherein B is substituted by a fluoro;
wherein R 1 is —(CR 5 R 6 ) n COOH;
wherein R 2 is CH 3 ;
wherein R 5 and R 6 are H; and
n is 1 or 2; and
wherein the systemic exposure is by intravenous administration.

4. A method of treating cancer in a patient in need thereof, wherein the method comprises administering to the patient a composition comprising a compound of formula (II), or a sodium salt thereof, wherein the compound of formula (II) has the following structure:

wherein R 1 is selected from the group consisting of CH 2 COOH and CH 2 CH 2 COOH;
wherein R 2 is CH 3 ; and
wherein R 3 is selected from the group consisting of 4-CH 2 CH 3 , and 4-CH(CH 3 ) 2 .

5. A method of treating cancer in a patient in need thereof, wherein the method comprises systemically exposing the patient to a compound of formula (II) wherein the compound of formula (II) has the following structure:

wherein R 1 is selected from the group consisting of CH 2 COOH and CH 2 CH 2 COOH;
wherein R 2 is CH 3 ; and
wherein R 3 is selected from the group consisting of 4-CH 2 CH 3 , and 4-CH(CH 3 ) 2 ;
and wherein the systemic exposure is by oral administration.

6. A method of treating cancer in a patient in need thereof, wherein the method comprises systemically exposing to the patient a compound of formula (II) wherein the compound of formula (II) has the following structure:

wherein R 1 is selected from the group consisting of CH 2 COOH and CH 2 CH 2 COOH;
wherein R 2 is CH 3 ; and
wherein R 3 is selected from the group consisting of 4-CH 2 CH 3 , and 4-CH(CH 3 ) 2 ;
and wherein the systemic exposure is by intravenous administration.

7. The method of any one of claims 1 , 2 , 3 , 4 , 5 , or 6 , wherein the cancer is selected from hormone-refractory-prostate cancer, prostate cancer, breast cancer, ovarian cancer, colon cancer, melanoma, skin cancer, lung cancer, hepatocarcinoma, acute myelogenous leukemia, bladder cancer, cervical cancer, cholangiocarcinoma, chronic myelogenous leukemia, colorectal cancer, gastric sarcoma, glioma, leukemia, lymphoma, multiple myeloma, osteosarcoma, pancreatic cancer, or stomach cancer.

8. The method of any one of claims 1 , 2 , 3 , 4 , 5 , or 6 , wherein the cancer is selected from lung cancer, breast cancer, prostate cancer, liver cancer, or colon cancer.

9. The method of any one of claims 1 , 2 , 3 , 4 , 5 , or 6 , wherein the cancer is selected from colon cancer or colorectal cancer.

10. The method of any one of claim 4 , 5 , or 6 , wherein the compound of formula (II), or a sodium salt thereof, is selected from the group consisting of:

11. The method of any one of claim 4 , 5 , or 6 , wherein the compound of formula (II), or a sodium salt thereof, is selected from the group consisting of:

12. The method of any one of claim 4 , 5 , or 6 , wherein the compound of formula (II), or a sodium salt thereof, has the following structure:

13. The method of any one of claim 4 , 5 , or 6 , wherein the compound of formula (II), or a sodium salt thereof, has the following structure:

14. A method of inducing apoptosis in a cell comprising contacting the cell with a compound of formula (I), wherein the compound of formula (I) has the following structure:

wherein A is a phenyl, and wherein A is substituted by one or two substituents independently selected from the group consisting of C2-3 alkyl, n-butyl, iso-butyl, sec-butyl, —CF 3 , a C3-C4 cycloalkyl, and a C4-C5 cycloalkylalkyl;
wherein B is a fused phenyl, and wherein B is substituted by a fluoro;
wherein R 1 is —(CR 5 R 6 ) n COOH;
wherein R 2 is CH 3 ;
wherein R 5 and R 6 are H; and
wherein n is 1 or 2.

15. The method of claim 14 wherein the cell is treated with TNF-α prior to contacting the cell with a compound of formula (I).

16. A method of suppressing the activity of AKT in a cell comprising contacting the cell with a compound of formula (I), wherein the compound of formula (I) has the following structure:

wherein A is a phenyl, and wherein A is substituted by one or two substituents independently selected from the group consisting of C2-3 alkyl, n-butyl, iso-butyl, sec-butyl, —CF 3 , a C3-C4 cycloalkyl, and a C4-C5 cycloalkyl

Assignees

• Sanford Burnham Prebys Medical Discovery Inst
• Univ Xiamen

Inventors

• Zhang Xiao-Kun
• Su Ying
• Zhou Hu
• Liu Wen
• Huang pei-qiang

Classifications

• A61K31/277

  having a ring, e.g. verapamil · CPC title

• A61K38/191

  Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta · CPC title

• A61K31/196

  the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• G01N33/5011

  for testing antineoplastic activity · CPC title