7DT2

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

7DT2 の概要

• エントリーDOI: 10.2210/pdb7dt2/pdb
• 分子名称: Tyrosine-protein kinase ABL1, [4-[5-[5-(dimethylcarbamoyl)pyridin-3-yl]-1H-pyrrolo[2,3-b]pyridin-3-yl]-2-methanoyl-5-methoxy-phenyl]boronic acid (3 entities in total)
• 機能のキーワード: tyrosine kinase covalent inhibitor chronic myelogenous leukemia, transferase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72678.19

構造登録者

Anantharajan, J.,Baburajendran, N. (登録日: 2021-01-04, 公開日: 2021-06-09, 最終更新日: 2023-11-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.3 Å)