Identification of novel, selective and potent Chk2 inhibitors

Gary Larson; Shunqi Yan; Huanming Chen; Frank Rong; Zhi Hong; Jim Zhen Wu

doi:10.1016/j.bmcl.2006.09.067

Identification of novel, selective and potent Chk2 inhibitors

Bioorg Med Chem Lett. 2007 Jan 1;17(1):172-5. doi: 10.1016/j.bmcl.2006.09.067. Epub 2006 Oct 10.

Authors

Gary Larson¹, Shunqi Yan, Huanming Chen, Frank Rong, Zhi Hong, Jim Zhen Wu

Affiliation

¹ Drug Discovery, Valeant Pharmaceutical Research and Development 3300 Hyland Avenue, Costa Mesa, CA 92626, USA.

PMID: 17035018
DOI: 10.1016/j.bmcl.2006.09.067

Abstract

A series of isothiazole carboxamidine compounds were synthesized and discovered as novel and selective inhibitors for Chk2. They are not active against the related Chk1 kinase. The structure-activity relationship studies were performed on the scaffold, and enzymatic kinetic analysis showed they are simple ATP competitive inhibitors with K(i) values as low as 11 nM for Chk2. Computer modeling studies were employed to comprehend the mechanism of action and SAR of these compounds.

MeSH terms

Adenosine Triphosphate / chemistry
Amidines / chemical synthesis
Amidines / chemistry*
Binding, Competitive
Checkpoint Kinase 2
Humans
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry*
Thiazoles / pharmacology

Substances

Amidines
Protein Kinase Inhibitors
Thiazoles
Adenosine Triphosphate
Checkpoint Kinase 2
CHEK2 protein, human
Protein Serine-Threonine Kinases