SSH-2 (slingshot-2) inhibitors and methods for making and using them

Patent metadata

Field	Value
Publication number	US-9487522-B2
Application number	US-201214005653-A
Country	US
Kind code	B2
Filing date	Mar 15, 2012
Priority date	Mar 18, 2011
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

In alternative embodiments, the invention provides compositions that inhibit the polypeptide SSH-2, or SlingSHot-2, a phosphatase enzyme that regulates actin filaments, and methods for making and using them, including methods comprising administering compositions of the invention to regulate or modify actin filament polymerization by inhibiting SSH-2, where in one embodiment compositions of the invention slow or inhibit F-actin depolymerization and severing. In alternative embodiments, compositions and methods of the invention are used to slow or inhibit cell motility and/or internal remodeling. In alternative embodiments, compositions and methods of the invention are used to slow or inhibit, or reverse, or ameliorate the progression of a cancer or a metastasis or other uncontrolled or unregulated cell growth, and/or Alzheimer's disease.

First claim

What is claimed is:

1. A pharmaceutical compound, a formulation, or a composition comprising: 3-[(4,5-dimethoxy-3-oxo-1H-isobenzofuran-1-yl)amino]-4-methylbenzoic acid; 2-ethoxy-5-(4-phenylpiperidine-1-sulfonyl)benzoic acid; 3-[bis(2-methoxyethyl)sulfamoyl]benzoic acid; or any combination thereof, or any analog or derivative thereof, or a stereoisomer or a bioisostere thereof.

2. A pharmaceutical compound, a formulation or a composition selected from the group consisting of:

wherein R1 and R2 can be any alkoxy group, methoxy- group, ethoxy- group, butoxy- group, or a group having a longer alkyl or alkene group; or any combination thereof, and R3 can be any alkyl group, including a methyl, ethyl, propyl or butyl or longer alkyl or alkene group, or any combination thereof;

wherein R1 can be any alkoxy group, including methoxy, ethoxy, butoxy, etc.) or having a longer alkyl or alkene group, or any combination thereof;

wherein R1 and R2 can be any alkoxy group, including methoxy, ethoxy, butoxy, etc.) or having a longer alkyl or alkene group, or any combination thereof;

3-[(4,5dimethoxy-3-oxo-1,3-dihydro-2-benzofuran-1-yl)amino]-4-methylbenzoic acid;

2-ethoxy-5-(4-phenylpiperidine-1-sulfonyl)benzoic acid;

3-[bis(2-methoxyethyl)sulfamoyl]benzoic acid;

wherein R1 can be any alkyl group, including a methyl, ethyl, propyl or butyl or longer alkyl or alkene group, or any combination thereof;

wherein Me is a methyl group and COO − is a carboxy group;

wherein R1 and R2 can be any alkyl group, including a methyl, ethyl, propyl or butyl or longer alkyl or alkene group, or any combination thereof;

wherein Me is a methyl group and COO − is a carboxy group;

wherein COO − is a carboxy group;

wherein R1, R2, R3, R4, and R5 can be any alkyl group, including a methyl, ethyl, propyl or butyl or longer alkyl or alkene group, or any combination thereof;

wherein Me is a methyl group and Et is an ethyl group;

wherein R1 can be any alkyl group, including a methyl, ethyl, propyl or butyl or longer alkyl or alkene group, or any combination thereof

3-[2-(2,6-dichlorophenoxy)ethyl]-4-oxophthalazine-1-carboxylate; ZINC03429974,

wherein Me is a methyl group and COO − is a carboxy group;
any combination thereof, and
any analog or derivative, or stereoisomer or bioisostere thereof.

3. The pharmaceutical compound, formulation or composition of claim 1 , formulated for enteral or parenteral administration; or formulated as a pill, tablet, geltab, powder, liquid, gel, aerosol or implant.

4. The pharmaceutical compound, formulation or composition of claim 2 , formulated for enteral or parenteral administration; or formulated as a pill, tablet, geltab, powder, liquid, gel, aerosol or implant.

5. A method for inhibiting or slowing the dephosphorylating of a cofilin, comprising:
providing a pharmaceutical formulation or composition compound a compound ZINC04307500 having the structure

and
(b) contacting the pharmaceutical compound, formulation or composition of (a) with a SSH-2 or SlingShot-2 polypeptide in an amount sufficient to inhibit or slow the dephosphorylating of the cofilin.

6. A method for inhibiting or slowing the dephosphorylating of a cofilin in a cell, comprising:
(i) (a) providing a pharmaceutical, formulation or composition
comprising a compound ZINC04307500 having the structure:

or any analog or derivative thereof or a stereoisomer or a bioisostere thereof; and
(b) contacting the pharmaceutical compound, formulation or composition of (a) with a SSH-2 or SlingShot-2 polypeptide in the cell in an amount sufficient to inhibit or slow the dephosphorylating of the cofilin; or
(ii) the method of (i), wherein the contacting of the compound or composition with the SSH-2 or SlingShot-2 polypeptide is in vitro, ex vivo or in vivo.

7. A method for inhibiting or preventing the binding of a cofilin to an F-actin, comprising:
(i) providing a pharmaceutical, formulation or composition
comprising a compound ZINC04307500 having the structure:

or any analog or derivative thereof or a stereoisomer or a bioisostere thereof; and
(b) contacting the pharmaceutical compound, formulation or composition of (a) with a SSH-2 or SlingShot-2 polypeptide in the cell in an amount sufficient to inhibit or slow the dephosphorylating of the cofilin, thereby inhibiting or preventing the binding of a cofilin to an F-actin; or
(ii) the method of (i), wherein the contacting of the compound or composition with the SSH-2 is in vitro, ex vivo or in vivo.

8. A method for inhibiting or preventing the binding of a cofilin to an F-actin, comprising:
(i) (a) providing a pharmaceutical, formulation or composition
comprising a compound ZINC04307500 having the structure:

and
(b) contacting the pharmaceutical compound, formulation or composition of (a) with a SSH-2 or SlingShot-2 polypeptide in the cell in an amount sufficient to inhibit or slow the dephosphorylating of the cofilin, thereby inhibiting or preventing the binding of a cofilin to an F-actin; or
(ii) the method of (i), wherein the contacting of the compound or composition with the SSH-2 is in vitro, ex vivo or in vivo.

9. A method for stabilizing F-actin polymers, actin filaments, or actin-comprising microtubules, in a cell, comprising:
(i) (a) providing a pharmaceutical, formulation or composition
comprising a compound ZINC04307500 having the structure:

or any an

Assignees

• Haga Jason H
• Chien Shu
• Mui Matt
• Levesque Marshall J
• Pham Phillip D
• Univ California

Inventors

• Haga Jason H
• Chien Shu
• Mui Matt
• Levesque Marshall J
• Pham Phillip D

Classifications

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D307/90

  with an oxygen atom in position 1 and a nitrogen atom in position 3, or vice versa · CPC title

• C07D237/32

  with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring · CPC title

• C07D211/96

  Sulfur atom · CPC title

• C07C311/17

  to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms · CPC title