title: New thiazole carboxamides as potent inhibitors of Akt kinases.
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.
authors.affiliation: 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.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chang
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Zhuang
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Luo
authors.forename: Xianwen
authors.initials: X
authors.lastname: Cao
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Tu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Lu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Ren
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3