L-45

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

Signaling Pathways >> Epigenetics >> Epigenetic Reader Domain

Research Areas >> Cancer

Brd:126 nM (Kd)

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. 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 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].

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].

[1]. Moustakim M, et al. Discovery of a PCAF Bromodomain Chemical Probe. Angew Chem Int Ed Engl. 2017 Jan 16;56(3):827-831.

(+)-JQ1 | GSK126 | Tazemetostat (EPZ-6438) | Birabresib (OTX015) | A 485 | Curcumin | ARV-771 | ARV-825 | I-BET762 | BI 2536 | GSK343 | C646 | 3-Deazaneplanocin A (hydrochloride) | I-BET151 | 666-15