Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors
| Autor(a) principal: | |
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| Data de Publicação: | 2020 |
| Outros Autores: | , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/50317 |
Resumo: | This journal is © The Royal Society of Chemistry 2020. |
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Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitorsThis journal is © The Royal Society of Chemistry 2020.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.Funded under the 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., project PTDC/MED-QUI/28764/2017 to J. D. S., 02/SAICT/2017 grant 28333 to T. R., doctoral studentship SFRH/BD/143583/2019 to B. B. S., and DL 57/2016/CP1451/CT0025 to J. D. S.). This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreements No. 807281 and 702428. The authors acknowledge the 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.), the Royal G. and Mae H. Westaway Family Memorial Fund (A. N. K.), National Science Foundation Graduate Research Fellowship (Grant No 1122374 to S. K. D.) and Ludwig Center at MIT's Koch Institute (S. K. D.). We also thank the High-Throughput Science Core at MIT supported by the Koch Institute Cancer Center Support Core Grant (P30-CA14051 to A. N. K.). The NMR spectrometers are part of the National NMR Facility, supported by Fundação para a Ciência e Technologic (RECI/BBB-BQB/0230/2012). The authors also thank ESRF and the ID30A-3 beamline staff for support with the X-ray data collection. iNOVA4Health – UID/Multi/04462/2013, a program financially supported by Fundação para a Ciência e Technologic/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.Royal Society of ChemistryRepositório da Universidade de LisboaSeixas, João D.Sousa, Bárbara B.Marques, Marta C.Guerreiro, AnaTraquete, RuiRodrigues, TiagoAlbuquerque, Inês S.Sousa, Marcos F. Q.Lemos, Ana R.Sousa, Pedro M. F.Bandeiras, Tiago M.Wu, DiDoyle, Shelby K.Robinson, Carol V.Koehler, Angela N.Corzana, FranciscoMatias, Pedro M.Bernardes, Gonçalo J. L.2021-12-09T16:11:22Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/50317engRSC Chem Biol. 2020 Aug 28;1(4):251-26210.1039/D0CB00033G2633-0679info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:54:26Zoai:repositorio.ul.pt:10451/50317Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:01:48.388603Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors |
| title |
Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors |
| spellingShingle |
Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors Seixas, João D. |
| title_short |
Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors |
| title_full |
Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors |
| title_fullStr |
Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors |
| title_full_unstemmed |
Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors |
| title_sort |
Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors |
| author |
Seixas, João D. |
| author_facet |
Seixas, João D. Sousa, Bárbara B. Marques, Marta C. Guerreiro, Ana Traquete, Rui Rodrigues, Tiago Albuquerque, Inês S. Sousa, Marcos F. Q. Lemos, Ana R. Sousa, Pedro M. F. Bandeiras, Tiago M. Wu, Di Doyle, Shelby K. Robinson, Carol V. Koehler, Angela N. Corzana, Francisco Matias, Pedro M. Bernardes, Gonçalo J. L. |
| author_role |
author |
| author2 |
Sousa, Bárbara B. Marques, Marta C. Guerreiro, Ana Traquete, Rui Rodrigues, Tiago Albuquerque, Inês S. Sousa, Marcos F. Q. Lemos, Ana R. Sousa, Pedro M. F. Bandeiras, Tiago M. Wu, Di Doyle, Shelby K. Robinson, Carol V. Koehler, Angela N. Corzana, Francisco Matias, Pedro M. Bernardes, Gonçalo J. L. |
| author2_role |
author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Seixas, João D. Sousa, Bárbara B. Marques, Marta C. Guerreiro, Ana Traquete, Rui Rodrigues, Tiago Albuquerque, Inês S. Sousa, Marcos F. Q. Lemos, Ana R. Sousa, Pedro M. F. Bandeiras, Tiago M. Wu, Di Doyle, Shelby K. Robinson, Carol V. Koehler, Angela N. Corzana, Francisco Matias, Pedro M. Bernardes, Gonçalo J. L. |
| description |
This journal is © The Royal Society of Chemistry 2020. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z 2021-12-09T16:11:22Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/50317 |
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http://hdl.handle.net/10451/50317 |
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eng |
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eng |
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RSC Chem Biol. 2020 Aug 28;1(4):251-262 10.1039/D0CB00033G 2633-0679 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Royal Society of Chemistry |
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Royal Society of Chemistry |
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