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8wyg

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Revision as of 11:31, 24 January 2024 by OCA (Talk | contribs)

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Crystal Structure of the second bromodomain of human BRD2 in complex with the inhibitor 22

Structural highlights

8wyg is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.13Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BRD2_HUMAN May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.^[1]

Publication Abstract from PubMed

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of pan-BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound 23 (IC(50) = 2.9 nM) exhibited a comparable BRD4 BD2 inhibitory activity relative to 10 (IC(50) = 1.0 nM) and remarkably improved selectivity over BRD4 BD1 (23: 2583-fold; 10: 344-fold). This lead compound significantly inhibited the proliferation of acute myeloid leukemia (AML) cell lines through induction of G0/G1 arrest and apoptosis in vitro. Excellent in vivo antitumor efficacy with 23 was achieved in an MV;411 mouse xenograft model. Pleasingly, compound 23 (hERG IC(50) > 30 muM) mitigated the inhibition of the human ether-a-go-go-related gene (hERG) ion channel compared with 10 (hERG IC(50) = 2.8 muM). This work provides a promising BD2-selective lead for the development of more effective and safe BET inhibitors as anticancer agents.

Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.,Jiang W, Hou Q, Xu H, Yang K, Wang X, Zhang K, Zeng Y, Li W, Wang B, Luo G, Zhao X, Shen H, Xu Y, Wu X J Med Chem. 2024 Jan 4. doi: 10.1021/acs.jmedchem.3c02104. PMID:38175809^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ LeRoy G, Rickards B, Flint SJ. The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol Cell. 2008 Apr 11;30(1):51-60. doi: 10.1016/j.molcel.2008.01.018. PMID:18406326 doi:10.1016/j.molcel.2008.01.018
↑ Jiang W, Hou Q, Xu H, Yang K, Wang X, Zhang K, Zeng Y, Li W, Wang B, Luo G, Zhao X, Shen H, Xu Y, Wu X. Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia. J Med Chem. 2024 Jan 4. PMID:38175809 doi:10.1021/acs.jmedchem.3c02104