5U2C

BRD4 second bromodomain (BD2) in complex with dual PI3 kinase (PI3K) inhibitor SF2558HA

5U2C の概要

• エントリーDOI: 10.2210/pdb5u2c/pdb
• 関連するPDBエントリー: 5U28 5U2E 5U2F
• 分子名称: Bromodomain-containing protein 4, N-hydroxy-4-[5-(morpholin-4-yl)-7-oxo-7H-thieno[3,2-b]pyran-3-yl]benzamide (2 entities in total)
• 機能のキーワード: bromodomain, transcription, inhibitor, epigenetics, transcription regulator-inhibitor complex, transcription regulator/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: O60885
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29149.68

構造登録者

Andrews, F.H.,Kutateladze, T.G. (登録日: 2016-11-30, 公開日: 2017-02-08, 最終更新日: 2024-03-06)

主引用文献

Andrews, F.H.,Singh, A.R.,Joshi, S.,Smith, C.A.,Morales, G.A.,Garlich, J.R.,Durden, D.L.,Kutateladze, T.G.
Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis.
Proc. Natl. Acad. Sci. U.S.A., 114:E1072-E1080, 2017

PubMed Abstract: is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.

PubMed: 28137841
DOI: 10.1073/pnas.1613091114

実験手法

X-RAY DIFFRACTION (3.3 Å)