Discovery of a PCAF bromodomain chemical probe

Journal article

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.

Authors: Moustakim, M; Clark, P; Trulli, L; Fuentes de Arriba, A; Ehebauer, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Angewandte Chemie International Edition
• Volume: 56
• Issue: 3
• Pages: 827–831
• Publication date: 2016-12-14
• DOI: 10.1002/anie.201610816
• EISSN: 1521-3773
• ISSN: 1433-7851
• Language: English
• Keywords: structure-based design; chemical probes; epigenetics; medicinal chemistry; bromodomains