7W7Y

The crystal structure of human abl1 kinase domain in complex with ABL2-A5

Summary for 7W7Y

• Entry DOI: 10.2210/pdb7w7y/pdb
• Descriptor: Tyrosine-protein kinase ABL1, 5-[3-(5-methanoyl-2-methoxy-4-oxidanyl-phenyl)-1~{H}-pyrrolo[2,3-b]pyridin-5-yl]-~{N},~{N}-dimethyl-pyridine-3-carboxamide (3 entities in total)
• Functional Keywords: abl1, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 64955.92

Authors

Zhu, C.,Zhang, Z.M. (deposition date: 2021-12-06, release date: 2022-04-27, Last modification date: 2024-10-23)

Primary citation

Chen, P.,Sun, J.,Zhu, C.,Tang, G.,Wang, W.,Xu, M.,Xiang, M.,Zhang, C.J.,Zhang, Z.M.,Gao, L.,Yao, S.Q.
Cell-Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR-ABL Kinase.
Angew.Chem.Int.Ed.Engl., 61:e202203878-e202203878, 2022

PubMed Abstract: 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.

PubMed: 35438229
DOI: 10.1002/anie.202203878

Experimental method

X-RAY DIFFRACTION (2.20003021871 Å)