New thiazole carboxamides as potent inhibitors of Akt kinases

Shaohua Chang; Zhang Zhang; Xiaoxi Zhuang; Jinfeng Luo; Xianwen Cao; Honglin Li; Zhengchao Tu; Xiaoyun Lu; Xiaomei Ren; Ke Ding

doi:10.1016/j.bmcl.2011.11.080

New thiazole carboxamides as potent inhibitors of Akt kinases

Bioorg Med Chem Lett. 2012 Jan 15;22(2):1208-12. doi: 10.1016/j.bmcl.2011.11.080. Epub 2011 Nov 30.

Authors

Shaohua Chang¹, Zhang Zhang, Xiaoxi Zhuang, Jinfeng Luo, Xianwen Cao, Honglin Li, Zhengchao Tu, Xiaoyun Lu, Xiaomei Ren, Ke Ding

Affiliation

¹ Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Science Park, Guangzhou 510530, China; Graduate School of Chinese Academy of Sciences, # 19 Yuquan Road, Beijing 100049, China.

PMID: 22172705
DOI: 10.1016/j.bmcl.2011.11.080

Abstract

A new series of 2-substituted thiazole carboxamides were identified as potent pan inhibitors against all three isoforms of Akt (Akt1, Akt2 and Akt3) by systematic optimization of weak screening hit N-(1-amino-3-phenylpropan-2-yl)-2-phenylthiazole-5-carboxamide (1). One of the most potent compounds, 5m, inhibited the kinase activities of Akt1, Akt2 and Akt3 with IC(50) values of 25, 196 and 24nM, respectively. The compound also potently inhibited the phosphorylation of downstream MDM2 and GSK3β proteins, and displayed strongly antiproliferative activity in prostate cancer cells. The inhibitors might serve as lead compounds for further development of novel effective anticancer agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Glycogen Synthase Kinase 3 / antagonists & inhibitors
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Humans
Models, Molecular
Molecular Structure
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 / metabolism
Structure-Activity Relationship
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Amides
Antineoplastic Agents
Protein Kinase Inhibitors
Thiazoles
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Proto-Oncogene Proteins c-akt
Glycogen Synthase Kinase 3