3 research outputs found
Discovery of a PCAF bromodomain chemical probe
The p300/CBPâassociated factor (PCAF) and related GCN5 bromodomainâcontaining lysine acetyl transferases are members of subfamilyâ
I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazineâbased Lâ45 (dubbed LâMoses) as the first potent, selective, and cellâactive PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)â(â)ânorephedrine furnished Lâ45 in enantiopure form. Lâ45 was shown to disrupt PCAFâBrd histone H3.3 interaction in cells using a nanoBRET assay, and a coâcrystal structure of Lâ45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound Lâ45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cellâpermeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for inâ
vivo use