Browsing by Author "Traquete, Rui"
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- Evaluation of linker length effects on a BET bromodomain probePublication . Traquete, Rui; Henderson, Elizabeth; Picaud, Sarah; Cal, Pedro M.S.D.; Sieglitz, Florian; Rodrigues, Tiago; Oliveira, Rudi; Filippakopoulos, Panagis; Bernardes, Gonçalo J. L.Fueled by the therapeutic potential of the epigenetic machinery, BET bromodomains have seen high interest as drug targets. Herein, we introduce different linkers to a BET bromodomain benzodiazepine ligand (I-BET762) to gauge its implications in the development of hybrid drugs, imaging probes and small molecule drug conjugates. Biophysical studies confirmed minimal disruption to binding of the BRD4 cavity by the synthesized entities, which includes imaging probes. Target engagement was confirmed in a cellular context, but poor membrane diffusion was found despite efficient localization in the nuclei after membrane disruption. Our study highlights challenges and opportunities for the successful design of benzodiazepine-derived drug-delivery systems.
- Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitorsPublication . 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.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.