Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe

• Published in: Journal of medicinal chemistry Vol. 60; no. 2; pp. 695 - 709
• Main Authors: Humphreys, Philip G, Bamborough, Paul, Chung, Chun-wa, Craggs, Peter D, Gordon, Laurie, Grandi, Paola, Hayhow, Thomas G, Hussain, Jameed, Jones, Katherine L, Lindon, Matthew, Michon, Anne-Marie, Renaux, Jessica F, Suckling, Colin J, Tough, David F, Prinjha, Rab K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.01.2017; Amer Chemical Soc
• Subjects: Animals; Cell Membrane Permeability; Chemistry, Medicinal; Histone Acetyltransferases - chemistry; Humans; Life Sciences & Biomedicine; Membranes, Artificial; Mice; Molecular Probes - chemical synthesis; Molecular Probes - chemistry; p300-CBP Transcription Factors - chemistry; Pharmacology & Pharmacy; Piperidines - chemical synthesis; Piperidines - chemistry; Protein Domains; Pyridazines - chemical synthesis; Pyridazines - chemistry; Science & Technology; Stereoisomerism; Structure-Activity Relationship; DESIGN; RECOGNITION; SMALL-MOLECULE INHIBITORS; PROGRESS; HIV-1 TAT; AMINO-ACID BIOSYNTHESIS; HISTONE ACETYLTRANSFERASE; PCAF; BINDING; CANCER
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01566

p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.