7CC2

Strategic design of catalytic lysine-targeting reversible covalent BCR-ABL Inhibitors

Summary for 7CC2

• Entry DOI: 10.2210/pdb7cc2/pdb
• Descriptor: Tyrosine-protein kinase ABL1, [4-[5-[5-(dimethylcarbamoyl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methyl-phenyl]boronic acid (3 entities in total)
• Functional Keywords: tyrosine kinase covalent inhibitor chronic myelogenous leukemia, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72590.17

Authors

Anantharajan, J.,Baburajendran, N. (deposition date: 2020-06-16, release date: 2021-06-09, Last modification date: 2024-10-23)

Primary citation

Quach, D.,Tang, G.,Anantharajan, J.,Baburajendran, N.,Poulsen, A.,Wee, J.L.K.,Retna, P.,Li, R.,Liu, B.,Tee, D.H.Y.,Kwek, P.Z.,Joy, J.K.,Yang, W.Q.,Zhang, C.J.,Foo, K.,Keller, T.H.,Yao, S.Q.
Strategic Design of Catalytic Lysine-Targeting Reversible Covalent BCR-ABL Inhibitors*.
Angew.Chem.Int.Ed.Engl., 60:17131-17137, 2021

PubMed Abstract: Targeted covalent inhibitors have re-emerged as validated drugs to overcome acquired resistance in cancer treatment. Herein, by using a carbonyl boronic acid (CBA) warhead, we report the structure-based design of BCR-ABL inhibitors via reversible covalent targeting of the catalytic lysine with improved potency against both wild-type and mutant ABL kinases, especially ABL bearing the gatekeeper residue mutation. We show the evolutionarily conserved lysine can be targeted selectively, and the selectivity depends largely on molecular recognition of the non-covalent pharmacophore in this class of inhibitors, probably due to the moderate reactivity of the warhead. We report the first co-crystal structures of covalent inhibitor-ABL kinase domain complexes, providing insights into the interaction of this warhead with the catalytic lysine. We also employed label-free mass spectrometry to evaluate off-targets of our compounds at proteome-wide level in different mammalian cells.

PubMed: 34008286
DOI: 10.1002/anie.202105383

Experimental method

X-RAY DIFFRACTION (2.723 Å)