Discovery of a PCAF bromodomain chemical probe

  • The p300/CBP‐associated factor (PCAF) and related GCN5 bromodomain‐containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine‐based L‐45 (dubbed L‐Moses) as the first potent, selective, and cell‐active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)‐(−)‐norephedrine furnished L‐45 in enantiopure form. L‐45 was shown to disrupt PCAF‐Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co‐crystal structure of L‐45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L‐45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell‐permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.
Author:Moses Moustakim, Peter G. K. Clark, Laura Trulli, Angel L. Fuentes de Arriba, Matthias T. Ehebauer, Apirat ChaikuadORCiD, Emma J. Murphy, Jacqui Mendez-Johnson, Danette Daniels, Chun-Feng D. Hou, Yu-Hui Lin, John R. Walker, Raymond Hui, Hongbing Yang, Lucy Dorrell, Catherine M. Rogers, Octovia Monteiro, Oleg Fedorov, Kilian Huber, Stefan Knapp, Jag Heer, Darren Dixon, Paul E. Brennan
Pubmed Id:
Parent Title (German):Angewandte Chemie. International edition
Place of publication:Weinheim
Document Type:Article
Year of Completion:2016
Date of first Publication:2016/12/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/10/18
Tag:Bromodomänen; Chemische Sonden; Epigenetik; Medizinische Chemie; Strukturbasiertes Design
bromodomains; chemical probes; epigenetics; medicinal chemistry; structure-based design
Page Number:5
First Page:827
Last Page:831
© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Identisch auch erschienen in der deutschsprachigen Ausgabe der Zeitschrift: Angewandte Chemie, 129.2017, S. 845–849, doi:10.1002/ange.201610816
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0