2. Academic Validation
  3. Discovery of 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides as novel RET kinase inhibitors

Discovery of 4-chloro-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl)benzamides as novel RET kinase inhibitors

  • Bioorg Med Chem Lett. 2016 Dec 1;26(23):5679-5684. doi: 10.1016/j.bmcl.2016.10.061.
Mei Han 1,  Shan Li 2,  Jing Ai 3,  Rong Sheng 2,  Yongzhou Hu 4,  Youhong Hu 5,  Meiyu Geng 6
Affiliations

Affiliations

  • 1 Department of Pharmacology and Glycobiology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 2 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.
  • 3 Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 27815117 DOI: 10.1016/j.bmcl.2016.10.061
Abstract

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.

Keywords

1,2,4-Oxadiazole; Anti-cancer therapy; RET kinase inhibitor.

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