Design of thienopyranone-based BET inhibitors that bind multiple synthetic lethality targets.

Autor: Vann KR; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA., Pal D; Division of Pediatric Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA., Morales GA; SignalRx Pharmaceuticals, San Diego, CA, USA., Burgoyne AM; Division of Hematology-Oncology, Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA., Durden DL; Division of Pediatric Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA. ddurden@ucsd.edu.; SignalRx Pharmaceuticals, San Diego, CA, USA. ddurden@ucsd.edu., Kutateladze TG; Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA. tatiana.kutateladze@cuanschutz.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Jul 21; Vol. 10 (1), pp. 12027. Date of Electronic Publication: 2020 Jul 21.
DOI: 10.1038/s41598-020-68964-6
Abstrakt: Development of small molecule compounds that target several cancer drivers has shown great therapeutic potential. Here, we developed a new generation of highly potent thienopyranone (TP)-based inhibitors for the BET bromodomains (BDs) of the transcriptional regulator BRD4 that have the ability to simultaneously bind to phosphatidylinositol-3 kinase (PI3K) and/or cyclin-dependent kinases 4/6 (CDK4/6). Analysis of the crystal structures of the complexes, NMR titration experiments and IC 50 measurements reveal the molecular basis underlying the inhibitory effects and selectivity of these compounds toward BDs of BRD4. The inhibitors show robust cytotoxic effects in multiple cancer cell lines and induce cell-cycle arrest and apoptosis. We further demonstrate that concurrent disruption of the acetyllysine binding function of BRD4 and the kinase activities of PI3K and CDK4/6 by the TP inhibitor improves efficacy in several cancer models. Together, these findings provide further compelling evidence that these multi-action inhibitors are efficacious and more potent than single inhibitory chemotypes.
Databáze: MEDLINE
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