ArticleChemMedChem2022
Dihydropyridine Lactam Analogs Targeting BET Bromodomains.
Article in ChemMedChem, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 4 citations in OpenAlex.
- Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors.Journal of medicinal chemistry · 2026Article
- 5-Amino- and 6-amino-uracils in the synthesis of various heterocycles as therapeutic agents: a review.RSC advances · 2025Review
- Macrocyclic dihydropyridine analogs as pan-BET BD2-preferred inhibitors.European journal of medicinal chemistry · 2025Article
- Synthesis and Characterization of Edaravone Analogues as Remyelinating Agents and Putative Mechanistic Probes.Molecules (Basel, Switzerland) · 2023Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
Abstract
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
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.