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Discovery of a PCAF Bromodomain Chemical Probe
Author(s) -
Moustakim Moses,
Clark Peter G. K.,
Trulli Laura,
Fuentes de Arriba Angel L.,
Ehebauer Matthias T.,
Chaikuad Apirat,
Murphy Emma J.,
MendezJohnson Jacqui,
Daniels Danette,
Hou ChunFeng D.,
Lin YuHui,
Walker John R.,
Hui Raymond,
Yang Hongbing,
Dorrell Lucy,
Rogers Catherine M.,
Monteiro Octovia P.,
Fedorov Oleg,
Huber Kilian V. M.,
Knapp Stefan,
Heer Jag,
Dixon Darren J.,
Brennan Paul E.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201610816
Subject(s) - bromodomain , pcaf , chemistry , subfamily , biochemistry , histone , cancer research , biology , gene
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.