Small molecule inhibitors of G(alpha)i2 protein and uses thereof

Patent metadata

Field	Value
Publication number	US-12084418-B2
Application number	US-202117556820-A
Country	US
Kind code	B2
Filing date	Dec 20, 2021
Priority date	Dec 21, 2020
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

The disclosure relates to novel compounds and methods of use of the compounds to maintain the Gα i 2 protein in its inactive GDP-bound state. The disclosure describes the knockdown or inhibition of Gα i 2 negatively regulated migration of breast and ovarian cancer cell lines. The novel compounds inhibit the migratory behavior of PC3, DU145 and E006AA prostate cancer cell lines. Specifically, the novel compounds block the activation of Gα i 2 in oxytocin-stimulated prostate cancer PC3 cells and inhibits the migratory capability of DU145 cells overexpressing constitutively active form of Gα i 2, under basal and EGF-stimulated conditions.

First claim

We claim:

1. A compound having the following structure:

2. A compound having the following structure:

3. A compound having the following structure:

4. A method of treating cancer, comprising administering to a subject in need thereof a compound of Formula I or Formula II:

wherein,
R 1 , R 2 and R 3 are each independently selected from the group consisting of H, OH and halogen;
R 4 is selected from the group consisting of H, alkyl, halo-alkyl, aryl, and pyridyl, wherein the aryl and pyridyl groups are optionally substituted at the ortho, meta and para positions;
R 5 is selected from the group consisting of H, methyl and ethyl;
R 6 is selected from the group consisting of H, OH and halogen; and
R 7 is OH or OMe;

wherein,
R 1a , R 2a and R 3a are each independently selected from the group consisting of H, OH and halogen;
R 4a is selected from the group consisting of H, alkyl, halo-alkyl, aryl and pyridyl, wherein the phenyl and pyridyl are optionally substituted at the ortho, meta and para positions;
R 5a is selected from the group consisting of H, methyl and ethyl;
R 6a is H or halogen;
R 7a is OH or OMe; and,
X is S or O;
to inhibit cell migration in prostate cancer, breast cancer, or ovarian cancer.

5. A method of treating cancer, comprising administering to a subject in need thereof a compound having the structure:

to inhibit cell migration in prostate cancer, breast cancer, or ovarian cancer.

6. The method of claim 4 , wherein
R 1 , R 2 and R 3 each independently selected from the group consisting of H, OH, Cl, Br and I;
R 4 is selected from the group consisting of H, methyl, ethyl, trifluoromethyl, phenyl and pyridyl, wherein the phenyl and pyridyl are optionally substituted at the ortho, meta and para positions;
R 5 is selected from the group consisting of H, methyl and ethyl;
R 6 is selected from the group consisting of H, OH, Cl, Br and I;
R 1a , R 2a and R 3a are each independently selected from the group consisting of H, OH, Cl, Br and I;
R 4a is selected from the group consisting of H, methyl, ethyl, trifluoromethyl, phenyl and pyridyl, wherein the phenyl and pyridyl are optionally substituted at the ortho, meta and para positions;
R 5a is selected from the group consisting of H, methyl and ethyl;
R 6a is selected from the group consisting of H, Cl, Br and I;
R 7a is OH or OMe; and,
X is S or O.

Assignees

• Clark Atlanta Univ Inc
• Georgia Tech Res Inst

Inventors

• Khan Shafiq A
• Caggia Silvia
• Oyelere Adegboyega K
• Tapadar Subhasish

Classifications

• C07D333/54

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D209/36 Primary

  in position 3, e.g. adrenochrome · CPC title

• C07D333/58

  Radicals substituted by nitrogen atoms · CPC title

• C07D209/14

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title