Discovery of 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides as novel RET kinase inhibitors.
A series of novel 4-chloro-benzamides derivatives containing substituted five-membered heteroaryl ring were designed, synthesized and evaluated as RET kinase inhibitors for cancer therapy. Most of compounds exhibited moderate to high potency in ELISA-based kinase assay. In particular, compound I-8 containing 1,2,4-oxadiazole strongly inhibited RET kinase activity both in molecular and cellular level. In turn, I-8 inhibited cell proliferation driven by RET wildtype and gatekeeper mutation. The results implied that 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides are promising lead compounds as novel RET kinase inhibitor for further investigation.
Department of Pharmacology and Glycobiology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Mei
M
Han
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Shan
S
Li
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
Jing
J
Ai
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Rong
R
Sheng
ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: huyz@zju.edu.cn.
Yongzhou
Y
Hu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 ZuChongZhi Road, Shanghai 201203, China. Electronic address: yhhu@simm.ac.cn.
Youhong
Y
Hu
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: mygeng@simm.ac.cn.
Meiyu
M
Geng
D000818:Animals; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D001549:Benzamides; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret
1,2,4-Oxadiazole; Anti-cancer therapy; RET kinase inhibitor