5U2C

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

Summary for 5U2C

• Entry DOI: 10.2210/pdb5u2c/pdb
• Related: 5U28 5U2E 5U2F
• Descriptor: 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)
• Functional Keywords: bromodomain, transcription, inhibitor, epigenetics, transcription regulator-inhibitor complex, transcription regulator/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus: O60885
• Total number of polymer chains: 2
• Total formula weight: 29149.68

Authors

Andrews, F.H.,Kutateladze, T.G. (deposition date: 2016-11-30, release date: 2017-02-08, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.3 Å)