2. Academic Validation
  3. Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

Targeting Cysteine Located Outside the Active Site: An Effective Strategy for Covalent ALKi Design

  • J Med Chem. 2021 Feb 11;64(3):1558-1569. doi: 10.1021/acs.jmedchem.0c01707.
Guoyi Yan 1 2,  Xinxin Zhong 1,  Chunlan Pu 1,  Lin Yue 1,  Huifang Shan 1,  Suke Lan 1,  Meng Zhou 3,  Xueyan Hou 4,  Jie Yang 1,  Deyu Li 2,  Shilong Fan 5,  Rui Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 2 Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, Zhengzhou, 450000, China.
  • 3 Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education & State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550000, China.
  • 4 College of Pharmacy, Xinxiang Medical University, Xinxiang, 453000, China.
  • 5 The Ministry of Education Key Laboratory of Protein Science, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center for Biological Structure, Collaborative Innovation Center for Biotherapy, School of Life Sciences, Tsinghua University, Beijing, 100000, China.
PMID: 33471528 DOI: 10.1021/acs.jmedchem.0c01707
Abstract

Potent inhibitors of ALK are highly desired because of the occurrence of drug resistance. We herein firstly report the development of a rationally designed inhibitor, Con B-1, which can covalently bind to Cys1259, a cysteine located outside the ALK active site by linking a warhead with Ceritinib through a 2,2'-Oxybis(ethylamine) linker. The in vitro and in vivo assays showed ConB-1 is a potent selective ALKi with low toxicity to normal cells. In addition, the molecule showed significant improvement of Anticancer activities and potential antidrug resistant activity compared with Ceritinib, demonstrating the covalent inhibitor of ALK can be a promising drug candidate for the treatment of NSCLC. This work may provide a novel perspective on the design of covalent inhibitors.

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