Discovery of a PCAF Bromodomain Chemical Probe

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• 作者：Moses Moustakim ; Dr. Peter G. K. Clark ; Laura Trulli ; Dr. Angel L. Fuentes de Arriba ; Dr. Matthias T. Ehebauer ; Dr. Apirat Chaikuad ; Dr. Emma J. Murphy ; Jacqui Mendez-Johnson ; Dr. Danette Daniels ; Dr. Chun-Feng D. Hou ; Yu-Hui Lin ; Dr. John R. Walker ; Dr. Raymond Hui ; Dr. Hongbing Yang ; Prof. Dr. Lucy Dorrell ; Dr. Catherine M. Rogers ; Octovia P. Monteiro ; Dr. Oleg Fedorov ; Dr. Kilian V. M. Huber ; Prof. Dr. Stefan Knapp ; Dr. Jag Heer ; Prof. Dr. Darren J. Dixon and Prof. Dr. Paul E. Brennan
• 刊名：Angewandte Chemie
• 出版年：2017
• 出版时间：January 16, 2017
• 年：2017
• 卷：129
• 期：3
• 页码：845-849
• 全文大小：1246K
• ISSN：1521-3757

文摘

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.