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
Discovery of a PCAF bromodomain chemical probe / Moustakim, Moses; Clark, Peter G. K.; Trulli, Laura; Fuentes de Arriba, Angel L.; Ehebauer, Matthias T.; Chaikuad, Apirat; Murphy, Emma J.; Mendez Johnson, Jacqui; Daniels, Danette; Hou, Chun Feng D.; Lin, Yu Hui; 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.. - In: ANGEWANDTE CHEMIE. INTERNATIONAL EDITION. - ISSN 1433-7851. - ELETTRONICO. - 56:3(2017), pp. 827-831. [10.1002/anie.201610816]
Discovery of a PCAF bromodomain chemical probe
TRULLI, LAURA;
2017
Abstract
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| File | Dimensione | Formato | |
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