Correlation Engine 2.0
Clear Search sequence regions

Sizes of these terms reflect their relevance to your search.

Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome. © 2022 Wiley-VCH GmbH.


Peng Chen, Jie Sun, Chengjun Zhu, Guanghui Tang, Wei Wang, Manyi Xu, Menghua Xiang, Chong-Jing Zhang, Zhi-Min Zhang, Liqian Gao, Shao Q Yao. Cell-Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR-ABL Kinase. Angewandte Chemie (International ed. in English). 2022 Jun 27;61(26):e202203878

Expand section icon Mesh Tags

Expand section icon Substances

PMID: 35438229

View Full Text