L-Moses

L-Moses (L-45) is the first potent, selective, and cell-active p300/CBP-associated factor (PCAF) bromodomain (Brd) inhibitor with a K_d of 126 nM^[1]. IC50 & Target: K_d:126±15nM (PCAF Brd-binding)^[1] In Vitro: L-Moses (L-45) disrupts PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-Moses with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. A structure using highly homologous (64 % identity) Brd from Plasmodium falciparum, PfGCN5, of which L-Moses is also a potent ligand (isothermal titration calorimetry (ITC) KD 280 nM), is successfully obtained (PDB: 5TPX). L-Moses binds in the acetylated lysines (KAc) -binding pocket of PfGCN (blue ribbon and sticks) and makes H-bonds (dotted lines) through the triazole to N1436 and the first of a network of four water molecules (red spheres)^[1]. In Vivo: L-Moses (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^[1].