Design and Characterization of Novel Covalent Bromodomain and Extra-Terminal Domain (BET) Inhibitors Targeting a Methionine

Journal of Medicinal Chemistry
Olesya A KharenkoPeter R Young

Abstract

BET proteins are key epigenetic regulators that regulate transcription through binding to acetylated lysine (AcLys) residues of histones and transcription factors through bromodomains (BDs). The disruption of this interaction with small molecule bromodomain inhibitors is a promising approach to treat various diseases including cancer, autoimmune and cardiovascular diseases. Covalent inhibitors can potentially offer a more durable target inhibition leading to improved in vivo pharmacology. Here we describe the design of covalent inhibitors of BRD4(BD1) that target a methionine in the binding pocket by attaching an epoxide warhead to a suitably oriented noncovalent inhibitor. Using thermal denaturation, MALDI-TOF mass spectrometry, and an X-ray crystal structure, we demonstrate that these inhibitors selectively form a covalent bond with Met149 in BRD4(BD1) but not other bromodomains and provide durable transcriptional and antiproliferative activity in cell based assays. Covalent targeting of methionine offers a novel approach to drug discovery for BET proteins and other targets.

References

Feb 7, 2009·Journal of Biomolecular Screening·Jingsong YangZhihong Lai
Apr 2, 2011·Nature Reviews. Drug Discovery·Juswinder SinghAdrian Whitty
Jun 20, 2012·FEBS Letters·Panagis Filippakopoulos, Stefan Knapp
Jan 7, 2014·PloS One·Kevin G McLurePeter R Young
Apr 23, 2014·Nature Reviews. Drug Discovery·Panagis Filippakopoulos, Stefan Knapp
Jun 7, 2014·Molecular Cell·Junwei Shi, Christopher R Vakoc
Jun 20, 2014·Future Oncology·Matthew S Davids, Jennifer R Brown
Mar 17, 2015·Angewandte Chemie·Jean-Pierre DaguerNicolas Winssinger
Jun 3, 2015·ACS Chemical Biology·Michael ZengerleAlessio Ciulli
Jun 9, 2015·Chemistry & Biology·Jing LuCraig M Crews
Jun 9, 2016·Proceedings of the National Academy of Sciences of the United States of America·Kanak RainaKevin G Coleman
Feb 12, 2017·Science·Shixian LinChristopher J Chang
Jun 14, 2017·Current Opinion in Chemical Biology·Roman LagoutteNicolas Winssinger
Aug 26, 2017·Annals of Oncology : Official Journal of the European Society for Medical Oncology·D B DoroshowP M LoRusso
Dec 14, 2017·Drug Discovery Today. Technologies·Olesya A Kharenko, Henrik C Hansen

❮ Previous
Next ❯

Citations

Nov 8, 2019·Current Topics in Medicinal Chemistry·Bingbing LiYuanxiang Wang
Dec 14, 2019·Chembiochem : a European Journal of Chemical Biology·Samuel E Dalton, Sebastien Campos
Sep 15, 2020·Medicinal Research Reviews·Ewelina KulikowskiNorman C W Wong
Dec 5, 2020·Future Medicinal Chemistry·Elena De Vita
Feb 19, 2021·Journal of Medicinal Chemistry·Yi ZhangYuanxiang Wang
Nov 15, 2019·Journal of Medicinal Chemistry·Jonathan PettingerMatthew D Cheeseman
Mar 26, 2019·Journal of Chemical Information and Modeling·Laurent HofferPhilippe Roche
Nov 11, 2021·Journal of Chemical Information and Modeling·Yun Lyna Luo

❮ Previous
Next ❯

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.

Related Papers

Chemical & Pharmaceutical Bulletin
Tomomi Noguchi-Yachide
The Journal of Biological Chemistry
Srimoyee GhoshJose M Lora
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Zhixiang ChengJialiang Wang
Biochemical and Biophysical Research Communications
Olesya A KharenkoHenrik C Hansen
© 2022 Meta ULC. All rights reserved