5MLI

N-TERMINAL BROMODOMAIN OF HUMAN BRD4 WITH 4-chloro-2-methyl-5-(methylamino)pyridazin-3(2H)-one

Summary for 5MLI

• Entry DOI: 10.2210/pdb5mli/pdb
• Descriptor: Bromodomain-containing protein 4, 4-chloranyl-2-methyl-5-(methylamino)pyridazin-3-one (3 entities in total)
• Functional Keywords: inhibitor, histone, epigenetic reader, bromodomain, brd4, bromodomain containing protein 4, antagonist, transcription
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 1
• Total formula weight: 15272.98

Authors

Chung, C.-W. (deposition date: 2016-12-06, release date: 2017-12-20, Last modification date: 2024-05-08)

Primary citation

Humphreys, P.G.,Bamborough, P.,Chung, C.W.,Craggs, P.D.,Gordon, L.,Grandi, P.,Hayhow, T.G.,Hussain, J.,Jones, K.L.,Lindon, M.,Michon, A.M.,Renaux, J.F.,Suckling, C.J.,Tough, D.F.,Prinjha, R.K.
Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe.
J. Med. Chem., 60:695-709, 2017

PubMed Abstract: 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.

PubMed: 28002667
DOI: 10.1021/acs.jmedchem.6b01566

Experimental method

X-RAY DIFFRACTION (1.63 Å)