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

Scientific Reports
Kendra R VannTatiana G Kutateladze

Abstract

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 IC50 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.

References

Jul 21, 2006·Acta Crystallographica. Section D, Biological Crystallography·Wladek MinorMaksymilian Chruszcz
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Sep 28, 2010·Nature·Panagis FilippakopoulosJames E Bradner
Nov 12, 2010·Nature·Edwige NicodemeAlexander Tarakhovsky
Feb 20, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Anna C BelkinaGerald V Denis
Mar 4, 2014·Nature Chemical Biology·Pietro CiceriStefan Knapp
Apr 23, 2014·Nature Reviews. Drug Discovery·Panagis Filippakopoulos, Stefan Knapp
Sep 15, 2015·Nature·Chun Yew FongMark A Dawson
Aug 26, 2016·Journal of Medicinal Chemistry·Luca Carlino, Giulio Rastelli
Feb 1, 2017·Proceedings of the National Academy of Sciences of the United States of America·Forest H AndrewsTatiana G Kutateladze
Feb 25, 2018·The Journal of Biological Chemistry·Grant R CampbellStephen A Spector
Dec 18, 2018·Molecular Cell·Jean-Philippe LambertAnne-Claude Gingras
Jan 17, 2020·Angewandte Chemie·Shipeng HeChunquan Sheng
Aug 15, 2020·Cell Discovery·Adam M BurgoyneDonald L Durden
Jul 29, 2021·Cell Discovery·Adam M BurgoyneDonald L Durden

❮ Previous
Next ❯

Methods Mentioned

BETA
flow cytometry
xenografts
NMR
xenograft
AlphaScreen

Software Mentioned

Phaser
PHENIX Refine
ModFit LT
Coot

Related Concepts

Related Feeds

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Related Papers

ACS Medicinal Chemistry Letters
Ahmed F Abdel-Magid
Expert Opinion on Therapeutic Patents
Tian LuCheng Luo
© 2021 Meta ULC. All rights reserved