Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity

Xianghong Guan, Narsihmulu Cheryala, Rezaul Md Karim, Alice Chan, Norbert Berndt, Jun Qi, Gunda I. Georg, Ernst Schönbrunn

Research output: Contribution to journalArticlepeer-review


Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription and chromatin remodeling. BET family members BRD4 and BRDT are validated targets for cancer and male contraceptive drug development, respectively. Due to the high structural similarity of the acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein-protein interactions induced by bivalent inhibitors may differ between BRD4 and BRDT, conferring an altered selectivity profile. Starting from nonselective monovalent inhibitors, we developed cell-active bivalent BET inhibitors with increased activity and selectivity for BRDT. X-ray crystallographic and solution studies revealed unique structural states of BRDT and BRD4 upon interaction with bivalent inhibitors. Varying spacer lengths and symmetric vs unsymmetric connections resulted in the same dimeric states, whereas different chemotypes induced different dimers. The findings indicate that the increased intra-BET selectivity of bivalent inhibitors is due to the differential plasticity of BET bromodomains upon inhibitor-induced dimerization.

Original languageEnglish (US)
Pages (from-to)10441-10458
Number of pages18
JournalJournal of medicinal chemistry
Issue number15
StatePublished - Aug 11 2022

Bibliographical note

Funding Information:
We thank the SER-CAT and GM/CA stations at Argonne National Laboratory for assistance with the synchrotron data collection and the Moffitt Chemical Biology Core for use of the crystallization and crystallography instruments (National Cancer Institute Grant P30-CA076292). This work was supported by the National Institute for Child Health & Human Development (Grant 5P50HD093540).

Publisher Copyright:
© 2022 American Chemical Society.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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