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

7MCF の概要

• エントリーDOI: 10.2210/pdb7mcf/pdb
• 分子名称: 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)
• 機能のキーワード: bromodomain-containing protein 4 isoform long, brd4, bromodomain containing protein 4, cap, hunk1, mcap, mitotic chromosome associated protein sgc, cell cycle
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31480.17

構造登録者

Sheriff, S. (登録日: 2021-04-02, 公開日: 2021-05-26, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.19 Å)