Cell‐Active, Irreversible Covalent Inhibitors Targeting a Surface‐Exposed Non‐Catalytic Lysine on Aurora a Kinase by Using Squarate Chemistry
Abstract
AbstractTargeting surface‐exposed lysines in kinases through covalent modification presents a major challenge due to their high pKa and inherently low reactivity. While current research primarily targets more reactive catalytic lysines buried in the ATP‐binding pocket, no systematic rational strategy has yet been developed for selectively engaging surface‐exposed lysines. Herein, we present a versatile strategy for developing cell‐active covalent kinase inhibitors (CKIs) by selectively targeting unique surface‐exposed lysines using squarate chemistry. By using Aurora A (AURKA) as a proof‐of‐concept, we systematically evaluated this approach against other well‐known lysine‐reactive warheads (e.g., EBA, SO2F, and OSO2F) and demonstrated, for the first time, squarates’ superior efficacy in engaging these challenging low‐reactivity lysines. Amongst various AURKA CKIs, AL8 emerged as the first‐in‐class squarate‐based, cell‐active inhibitor, exhibiting excellent selectivity in both biochemical and cellular assays with long‐residence time in covalently engaging endogenous AURKA. Detailed investigation of effects of leaving groups on squaric esters provided valuable insights for future development of lysine‐reactive CKIs. Our finding has established squarate‐containing ligands as a unique and readily tunable platform for covalent modification of surface‐exposed, non‐catalytic lysines in targeted kinase drug discovery.
Article Details
Authors (13)
Zuqin Wang
State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, School of Pharmacy Jinan University #855 Xingye Avenue Guangzhou 510632 China
Xuan Wang
Yong Li
Peishan Li
Shengjie Huang
State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences Chinese Academy of Sciences Shanghai P. R. China
Peng Chen
Guanghui Tang
Department of Chemistry, National University of Singapore 4 Science Drive 2 Singapore 117543 Singapore
Xiaotong Ding
State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, School of Pharmacy Jinan University #855 Xingye Avenue Guangzhou 510632 China
Zhang Zhang
State Key Laboratory of Bioactive Molecules and Druggability Assessment, and School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
Zhi‐Min Zhang
State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, School of Pharmacy Jinan University #855 Xingye Avenue Guangzhou 510632 China
Yang Zhou
Shao Q. Yao
Department of Chemistry, National University of Singapore, 4 Science Drive 2, Singapore 117544, Singapore
Xiaoyun Lu
School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China