Discovery of a potent and highly selective inhibitor of ataxia telangiectasia mutated and Rad3-Related (ATR) kinase: Structural activity relationship and antitumor activity both in vitro and in vivo

  • Eur J Med Chem. 2022 Mar 15;232:114187. doi: 10.1016/j.ejmech.2022.114187.
Huachao Bin  1 ,  Pei Chen  2 ,  Ming Wu  1 ,  Falu Wang  1 ,  Guifeng Lin  1 ,  Shulei Pan  1 ,  Jingming Liu  1 ,  Bo Mu  1 ,  Jinshan Nan  1 ,  Qiao Huang  2 ,  Linli Li  3 ,  Shengyong Yang  4
Affiliations
  • 1. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 2. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 3. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: [email protected].
PMID: 35183872 DOI: 10.1016/j.ejmech.2022.114187
Abstract

Ataxia telangiectasia mutated and Rad3-related (ATR) kinase is an important regulator of the DNA damage response (DDR), especially in response to replication stress (RS). Tumor cells with ataxia-telangiectasia mutated (ATM) kinase loss of function or DDR defects that promote replicative stress are often more reliant on ATR for survival, highlighting ATR as a good antitumor target under the principle of synthetic lethality. Herein we report the discovery of a potent and highly selective ATR Inhibitor, SKLB-197, which was obtained through structural optimization and structure-activity relationship (SAR) studies towards a hit compound (Cpd-1). SKLB-197 showed an IC50 value of 0.013 μM against ATR but very weak or no activity against Other 402 protein kinases. It displayed potent antitumor activity against ATM-deficent tumors both in vitro and in vivo. In addition, this compound exhibited good pharmacokinetic properties. Overall, SKLB-197 could be a promising lead compound for drug discovery targeting ATR and deserves further in-depth studies.

Keywords
ATR inhibitor; Antitumor efficacy; Structural activity relationship; Synthetic lethality.
Products