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Issue 4, 2020
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Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors

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Abstract

The bone marrow tyrosine kinase in chromosome X (BMX) is pursued as a drug target because of its role in various pathophysiological processes. We designed BMX covalent inhibitors with single-digit nanomolar potency with unexploited topological pharmacophore patterns. Importantly, we reveal the first X-ray crystal structure of covalently inhibited BMX at Cys496, which displays key interactions with Lys445, responsible for hampering ATP catalysis and the DFG-out-like motif, typical of an inactive conformation. Molecular dynamic simulations also showed this interaction for two ligand/BMX complexes. Kinome selectivity profiling showed that the most potent compound is the strongest binder, displays intracellular target engagement in BMX-transfected cells with two-digit nanomolar inhibitory potency, and leads to BMX degradation PC3 in cells. The new inhibitors displayed anti-proliferative effects in androgen-receptor positive prostate cancer cells that where further increased when combined with known inhibitors of related signaling pathways, such as PI3K, AKT and Androgen Receptor. We expect these findings to guide development of new selective BMX therapeutic approaches.

Graphical abstract: Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors

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Article information


Submitted
26 Mar 2020
Accepted
21 Aug 2020
First published
28 Aug 2020

This article is Open Access

RSC Chem. Biol., 2020,1, 251-262
Article type
Paper

Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors

J. D. Seixas, B. B. Sousa, M. C. Marques, A. Guerreiro, R. Traquete, T. Rodrigues, I. S. Albuquerque, M. F. Q. Sousa, A. R. Lemos, P. M. F. Sousa, T. M. Bandeiras, D. Wu, S. K. Doyle, C. V. Robinson, A. N. Koehler, F. Corzana, P. M. Matias and G. J. L. Bernardes, RSC Chem. Biol., 2020, 1, 251
DOI: 10.1039/D0CB00033G

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