7DN4

The crystal structure of Cpd8 in complex with BPTF bromodomain

Summary for 7DN4

• Entry DOI: 10.2210/pdb7dn4/pdb
• Descriptor: Nucleosome-remodeling factor subunit BPTF, 3-methyl-2-[[(3R,5R)-1-methyl-5-phenyl-piperidin-3-yl]amino]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-one (2 entities in total)
• Functional Keywords: inhibitor, bptf, bromodomain, reader, protein binding
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 88763.17

Authors

Xiong, L.,Guo, Y.,Yang, S. (deposition date: 2020-12-08, release date: 2021-10-20, Last modification date: 2023-11-29)

Primary citation

Xiong, L.,Mao, X.,Guo, Y.,Zhou, Y.,Chen, M.,Chen, P.,Yang, S.,Li, L.
Discovery of selective BPTF bromodomain inhibitors by screening and structure-based optimization.
Biochem.Biophys.Res.Commun., 545:125-131, 2021

PubMed Abstract: Bromodomain and PHD finger containing transcription factor (BPTF) is a multidomain protein that regulates the transcription of chromatin and is related to many cancers. Herein, we report the screening-based discovery of Cpd1, a compound with micromolar affinity to the BPTF bromodomain. Through structure-guided optimization, we synthesized a variety of new inhibitors. Among these compounds, Cpd8 and Cpd10 were highly potent and selective inhibitors, with K values of 428 nM and 655 nM in ITC assays, respectively. The high activity was explained by the cocrystal structure of Cpd8 in complex with the BPTF bromodomain protein. Cpd8 and Cpd10 were able to stabilize the BPTF bromodomain protein in cells in a cellular thermal shift assay (CETSA). Cpd8 downregulated c-MYC expression in A549 cells. All experiments prove that these two compounds are potential BPTF inhibitors.

PubMed: 33548625
DOI: 10.1016/j.bbrc.2021.01.067

Experimental method

X-RAY DIFFRACTION (2.841 Å)