Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors
Year: 2020
Type: article
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.
Source: RSC Chemical Biology
DOI: 10.1039/d0cb00033g
Authors: João D. Seixas, Bárbara B. Sousa, Marta C. Marques, Ana Guerreiro, Rui Traquete, Tiago Rodrigues, Inês S. Albuquerque, Marcos F. Q. Sousa, Ana R. Lemos, Pedro M. F. Sousa, Tiago M. Bandeiras, Di Wu, Shelby K. Doyle, Carol V. Robinson, Angela N. Koehler, Francisco Corzana, Pedro M. Matias, Gonçalo J. L. Bernardes
Institutions: University of Lisbon, Instituto de Medicina Molecular João Lobo Antunes, Instituto de Biologia Experimental e Tecnológica, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, University of Oxford, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, Universidad de La Rioja, University of Cambridge
Language: English
Subfield: Computational Theory and Mathematics
Field: Computer Science
Domain: Physical Sciences
Open Access status: gold
Estimated APC paid: $1,962
Funders: National Science Foundation, Wellcome Trust, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Royal Society, European Commission, European Synchrotron Radiation Facility, Ministerio de Economía y Competitividad, Ministério da Ciência, Tecnologia e Ensino Superior, Ludwig Center at Harvard, Fundação para a Ciência e a Tecnologia, National Cancer Institute, H2020 Spreading Excellence and Widening Participation, H2020 Marie Skłodowska-Curie Actions
Awards: G105728699, G1297482482, G1483381719, G1516346500, G1690109813, BMX-targeted ligand-drug conjugates for prostate cancer therapy, BMX-targeted ligand-drug conjugates for prostate cancer therapy, Combinatorial Antibody Synthesis for the discovery of Targeted Immunomodulators, G2360436881, G2592574724, G2673245850, G2734793695, G2759452159, G2978044543, The effects of drug and lipid binding on the structure and function of membrane proteins in health and disease ., G3451420746, Graduate Research Fellowship Program, G3589480356, G3891694003, G4197248613, G434337789, A Small Molecule Drug Conjugate (SMDC) for Prostate Cancer Therapy, G5108852245, Nanoparticle-Based Therapeutic Applications and Detection of Carbon Monoxide Releasing Molecules, G5389921940, G5454278309, G5572498632, Entrega Intracelular de Fármacos usando Conjugados entre Pequenas Moléculas e Fármacos para Terapia do Cancro da Próstata, NMR Net - Centro Nacional de Ressonância Magnética Nuclear: desde a Estrutura e Dinâmica Moleculares à Função Proteica, Fisiologia Celular e Metabolómica, Nanoparticle-Based Therapeutic Applications and Detection of Carbon Monoxide Releasing Molecules, G7858748947, The effects of drug and lipid binding on the structure and function of membrane proteins in health and disease ., Sem título, TRPV1-targeted ligand-drug conjugates to treat prostate cancer, G8778376598, G8839327758, Cancer Center Support (Core) Grant, G946021960
OpenAlex ID: W3082052009