7MCF

CRYSTAL STRUCTURE OF THE FIRST BROMODOMAIN OF HUMAN BRD4 IN COMPLEX WITH 2-{3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol

Summary for 7MCF

• Entry DOI: 10.2210/pdb7mcf/pdb
• Descriptor: Bromodomain-containing protein 4, 2-{3-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-fluoro-5-[(S)-(3-fluoropyridin-2-yl)(oxan-4-yl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (3 entities in total)
• Functional Keywords: bromodomain-containing protein 4 isoform long, brd4, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein sgc, cell cycle
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 31480.17

Authors

Sheriff, S. (deposition date: 2021-04-02, release date: 2021-05-26, Last modification date: 2023-10-18)

Primary citation

Hill, M.D.,Fang, H.,Tokarski, J.,Fanslau, C.,Haarhoff, Z.,Huang, C.,Kramer, M.,Menard, K.,Monereau, L.,Morrison, J.,Ranasinghe, A.,Shields, E.E.,Tye, C.K.,Westhouse, R.,Everlof, G.,Sheriff, S.,Yan, C.,Marsilio, F.,Zhang, L.,Zvyaga, T.,Lee, F.,Gavai, A.V.,Degnan, A.P.
Development of BET inhibitors as potential treatments for cancer: A search for structural diversity.
Bioorg.Med.Chem.Lett., 44:128108-128108, 2021

PubMed Abstract: We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12, that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg.

PubMed: 33991625
DOI: 10.1016/j.bmcl.2021.128108

Experimental method

X-RAY DIFFRACTION (2.19 Å)