L-45 is the first potent and cell-active bromodomain (Brd) inhibitor of p300/CBP-associated factor (PCAF) (Kd: 126±15 nM).

BRD:126 nM (kd)

L-45 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). A structure using highly homologous (64?% identity) Brd from Plasmodium falciparum, PfGCN5, of which L-45 is also a potent ligand (isothermal titration calorimetry (ITC) KD 280 nM), is successfully obtained (PDB: 5TPX). L-45 disrupts 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 [1].

In human and mouse liver microsomes, L-45 displays no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability. It also supports its potential for in vivo use[1].