TY  - JOUR
A1  - Moustakim, Moses
A1  - Clark, Peter G. K.
A1  - Trulli, Laura
A1  - Fuentes de Arriba, Angel L.
A1  - Ehebauer, Matthias T.
A1  - Chaikuad, Apirat
A1  - Murphy, Emma J.
A1  - Mendez-Johnson, Jacqui
A1  - Daniels, Danette
A1  - Hou, Chun-Feng D.
A1  - Lin, Yu-Hui
A1  - Walker, John R.
A1  - Hui, Raymond
A1  - Yang, Hongbing
A1  - Dorrell, Lucy
A1  - Rogers, Catherine M.
A1  - Monteiro, Octovia
A1  - Fedorov, Oleg
A1  - Huber, Kilian
A1  - Knapp, Stefan
A1  - Heer, Jag
A1  - Dixon, Darren
A1  - Brennan, Paul E.
T1  - Discovery of a PCAF bromodomain chemical probe
T2  - Angewandte Chemie. International edition
N2  - 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.
KW  - bromodomains
KW  - chemical probes
KW  - epigenetics
KW  - medicinal chemistry
KW  - structure-based design
KW  - Bromodomänen
KW  - Chemische Sonden
KW  - Epigenetik
KW  - Medizinische Chemie
KW  - Strukturbasiertes Design
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47700
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-477006
SN  - 1521-3773
SN  - 1433-7851
N1  - © 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.
N1  - Identisch auch erschienen in der deutschsprachigen Ausgabe der Zeitschrift: Angewandte Chemie, 129.2017, S. 845–849, doi:10.1002/ange.201610816
VL  - 56
IS  - 3
SP  - 827
EP  - 831
PB  - Wiley-VCH
CY  - Weinheim
ER  -