Dihydropyridine Lactam Analogs Targeting BET Bromodomains

Jiewei Jiang, Logan H. Sigua, Alice Chan, Prakriti Kalra, William C.K. Pomerantz, Ernst Schönbrunn, Jun Qi, Gunda I. Georg

Research output: Contribution to journalArticlepeer-review


Inhibitors of Bromodomain and Extra Terminal (BET) proteins are investigated for various therapeutic indications, but selectivity for BRD2, BRD3, BRD4, BRDT and their respective tandem bromodomains BD1 and BD2 remains suboptimal. Here we report selectivity-focused structural modifications of previously reported dihydropyridine lactam 6 by changing linker length and linker type of the lactam side chain in efforts to engage the unique arginine 54 (R54) residue in BRDT-BD1 to achieve BRDT-selective affinity. We found that the analogs were highly selective for BET bromodomains, and generally more selective for the first (BD1) and second (BD2) bromodomains of BRD4 rather than for those of BRDT. Based on AlphaScreen and BromoScan results and on crystallographic data for analog 10 j, we concluded that the lack of selectivity for BRDT is most likely due to the high flexibility of the protein and the unfavorable trajectory of the lactam side chain that do not allow interaction with R54. A 15-fold preference for BD2 over BD1 in BRDT was observed for analogs 10 h and 10 m, which was supported by protein-based 19F NMR experiments with a BRDT tandem bromodomain protein construct.

Original languageEnglish (US)
Article numbere202100407
Issue number1
StatePublished - Jan 5 2022

Bibliographical note

Funding Information:
This project was supported by the NIH/NICHD: HHSN275201300017C and 5P50HD093540 from the Contraception Research Branch and from NIH/GM 1R35GM140837. We thank the Moffitt Chemical Biology Core for use of the protein crystallography facility (NCI grant 5P30‐CA076292).

Publisher Copyright:
© 2021 Wiley-VCH GmbH

PubMed: MeSH publication types

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


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