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Rationally Designed Potent BMX Inhibitors Reveals Mode of Covalent Binding at the Atomic Level

submitted on 09.01.2020, 10:20 and posted on 09.01.2020, 17:02 by João D. Seixas, Bárbara B. Sousa, Marta C. Marques, Ana Guerreiro, Rui Traquete, Tiago Rodrigues, Inês S. Albuquerque, Marcos Sousa, Ana R. Lemos, Pedro M. F. Sousa, Tiago M. Bandeiras, Di Wu, Shelby K. Doyle, Carol V. Robinson, Angela Koehler, Francisco Corzana, Pedro Matias, Gonçalo Bernardes

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 JS25 is the strongest binder and displays intracellular target engagement in BMX-transfected cells with two-digit nanomolar inhibitory potency. 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.


Royal Society (URF to G.J.L.B., URF\R\180019)

FCT Portugal (iFCT to G.J.L.B., IF/00624/2015, Postdoctoral Fellowship SFRH/BPD/95253/2013 to J.D.S., PTDC/MED-QUI/28764/2017 to J.D.S. and 02/SAICT/2017 grant 28333 to T.R.)

Marie Sklodowska-Curie IF (grant agreement No. 702428 to J.D.S. and No. 743640 to T.R.)

H2020 (TWINN-2017 ACORN, grant 807281 to T.R.)

Wellcome Trust (104633/Z/14/Z, to D.W. and C.V.R.)

Ministerio de Economía y Competitividad (project RTI2018-099592-B-C21 to F.C.)

Royal G. and Mae H. Westaway Family Memorial Fund (A.N.K.)

High-Throughput Science Core at MIT supported by the Koch Institute Cancer Center Support Core Grant (P30-CA14051 to A.N.K.)

National NMR Facility, supported by Fundação para a Ciência e Tecnologia (RECI/BBB-BQB/0230/2012)

iNOVA4Health - UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Tecnologia / Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement , and MOSTMICRO (project LISBOA-01-0145-FEDER-007660) co-funded by FCT/MCTES and FEDER funds through COMPETE2020—Programa Operacional Competitividade e Internacionalização (POCI) are also acknowledged.


Email Address of Submitting Author


University of Cambridge


United Kingdom

ORCID For Submitting Author


Declaration of Conflict of Interest

J.D.S. and G.J.L.B. are inventors in a patent application related to the findings reported in this manuscript. Other authors declare no competing interests.