Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors

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• 作者：F. Anthony Romero ; Alexander M. Taylor ; Terry D. Crawford ; Vickie Tsui ; Alexandre Côté ; Steven Magnuson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：February 25, 2016
• 年：2016
• 卷：59
• 期：4
• 页码：1271-1298
• 全文大小：1270K
• 年卷期：F. Anthony Romero
  is a medicinal chemist at Genentech in South San Francisco, California. He earned his A.B. from Occidental College and Ph.D. from the University of Kansas under Prof. Gary Grunewald. He did a postdoctoral fellowship at The Scripps Research Institute with Prof. Dale Boger and worked at Merck prior to joining Genentech.
  Alexander M. Taylor
  is a medicinal chemist at Constellation Pharmaceuticals in Cambridge, Massachusetts. He received a B.Sc. in chemistry from Vanderbilt University in Nashville, Tennessee and worked with Bernd Giese at the University of Basel in Switzerland before joining the group of Prof. Stuart Schreiber in the chemistry department at Harvard University for his Ph.D. work. He conducted postdoctoral research with Prof. Stephen Buchwald at MIT before joining Constellation Pharmaceuticals.
  Terry D. Crawford
  is a medicinal chemist at Genentech in South San Francisco, California. He earned his B.Sc. from the University of Nebraska, Lincoln, and worked at Pfizer prior to joining Genentech.
  Vickie Tsui
  is a computational chemist at Genentech in South San Francisco, California. She earned her B.Sc. from Yale University and her Ph.D. from The Scripps Research Institute under Prof. David Case.
  Alexandre Côté
  is a medicinal chemist at Constellation Pharmaceuticals in Cambridge, Massachusetts. He earned his B.Sc. degree from Université Laval and his M.Sc. and Ph.D. degrees from Université de Montréal under the supervision of Prof. André B. Charette. He did a postdoctoral fellowship at Princeton University with Prof. Erik J. Sorensen and worked at Pharmacor and Infinity Pharmaceuticals prior to joining Constellation Pharmaceuticals.
  Steven Magnuson
  is a medicinal chemist at Genentech in South San Francisco, California. He earned his B.Sc. from the University of British Columbia and his Ph.D. from the University of Alberta with Prof. Derek Clive. He did a postdoctoral fellowship at Columbia University with Prof. Samuel Danishefsky and worked at Bayer prior to joining Genentech.
• ISSN：1520-4804

文摘

Bromodomains, small protein modules that recognize acetylated lysine on histones, play a significant role in the epigenome, where they function as “readers” that ultimately determine the functional outcome of the post-translational modification. Because the initial discovery of selective BET inhibitors have helped define the role of that protein family in oncology and inflammation, BET bromodomains have continued to garner the most attention of any other bromodomain. More recently, non-BET bromodomain inhibitors that are potent and selective have been disclosed for ATAD2, CBP, BRD7/9, BRPF, BRPF/TRIM24, CECR2, SMARCA4, and BAZ2A/B. Such novel inhibitors can be used to probe the physiological function of these non-BET bromodomains and further understanding of their role in certain disease states. Here, we provide an update to the progress in identifying selective bromodomain inhibitors and their use as biological tools, as well as our perspective on the field.