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Discovery of a PCAF Bromodomain Chemical Probe

Discovery of a PCAF Bromodomain Chemical Probe

Moses Moustakim, Peter G K Clark, Laura Trulli, Angel L Fuentes de Arriba, Matthias T Ehebauer, Apirat Chaikuad, Emma J Murphy, Jacqui Mendez-Johnson, Danette Daniels, Chun-Feng D Hou, Yu-Hui Lin, John R Walker, etc.

Angew Chem Int Ed Engl. 2017 Jan 16;56(3):827-831.

PMID: 27966810

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP2079885053	L-Moses		2079885-05-3	Price

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