6CKR

Crystal Structure of BRD4 with QC4956

Summary for 6CKR

• Entry DOI: 10.2210/pdb6ckr/pdb
• Descriptor: Bromodomain-containing protein 4, N-{3-[2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1-oxo-1,2-dihydroisoquinolin-4-yl]phenyl}methanesulfonamide (3 entities in total)
• Functional Keywords: brd4, acetyllysine, epigenetics, gene regulation-inhibitor complex, gene regulation/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 2
• Total formula weight: 30841.55

Authors

Hosfield, D.J. (deposition date: 2018-02-28, release date: 2018-05-02, Last modification date: 2023-10-04)

Primary citation

Bennett, M.J.,Wu, Y.,Boloor, A.,Matuszkiewicz, J.,O'Connell, S.M.,Shi, L.,Stansfield, R.K.,Del Rosario, J.R.,Veal, J.M.,Hosfield, D.J.,Xu, J.,Kaldor, S.W.,Stafford, J.A.,Betancort, J.M.
Design, synthesis and biological evaluation of novel 4-phenylisoquinolinone BET bromodomain inhibitors.
Bioorg. Med. Chem. Lett., 28:1811-1816, 2018

PubMed Abstract: The bromodomain and extra-terminal (BET) family of epigenetic proteins has attracted considerable attention in drug discovery given its involvement in regulating gene transcription. Screening a focused small molecule library based on the bromodomain pharmacophore resulted in the identification of 2-methylisoquinoline-1-one as a novel BET bromodomain-binding motif. Structure guided SAR exploration resulted in >10,000-fold potency improvement for the BRD4-BD1 bromodomain. Lead compounds exhibited excellent potencies in both biochemical and cellular assays in MYC-dependent cell lines. Compound 36 demonstrated good physicochemical properties and promising exposure levels in exploratory PK studies.

PubMed: 29657099
DOI: 10.1016/j.bmcl.2018.04.016

Experimental method

X-RAY DIFFRACTION (1.62 Å)