ArticleProceedings of the National Academy of Sciences of the United States of America2022
Discovery of potent BET bromodomain 1 stereoselective inhibitors using DNA-encoded chemical library selections.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 34 citations in OpenAlex.
- Targeting bromodomain and extraterminal proteins in cardiovascular disease: Pathological mechanisms and therapeutic applications.The Journal of international medical research · 2026Review
- Toward the Chemoenzymatic Synthesis of DNA-Encoded Libraries.ACS central science · 2026Review
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Macrocyclic dihydropyridine analogs as pan-BET BD2-preferred inhibitors.European journal of medicinal chemistry · 2025Article
- Non-hormonal Contraception: Current and Emerging Targets.Advances in experimental medicine and biology · 2025Review
- Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Advances in Male Contraception: When Will the Novel Male Contraception be Available?The world journal of men's health · 2024Review
- Identification of potent pan-ephrin receptor kinase inhibitors using DNA-encoded chemistry technology.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- A bromodomain-independent mechanism of gene regulation by the BET inhibitor JQ1: direct activation of nuclear receptor PXR.Nucleic acids research · 2024Article
- DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors.Communications chemistry · 2023Article
- Crystal structure of [1,2,4]triazolo[4,3-b]pyridazine derivatives as BRD4 bromodomain inhibitors and structure-activity relationship study.Scientific reports · 2023Article
- Recent progress and structural analyses of domain-selective BET inhibitors.Medicinal research reviews · 2023Review
- Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins.Molecular therapy. Nucleic acids · 2023Article
- Reproductive genomics of the mouse: implications for human fertility and infertility.Development (Cambridge, England) · 2023Article
- Discovery of Highly Potent and BMPR2-Selective Kinase Inhibitors Using DNA-Encoded Chemical Library Screening.Journal of medicinal chemistry · 2023Article
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Authors and funding
21 authors at 1 institution in 1 country.
Funding
Abstract
BRDT, BRD2, BRD3, and BRD4 comprise the bromodomain and extraterminal (BET) subfamily which contain two similar tandem bromodomains (BD1 and BD2). Selective BD1 inhibition phenocopies effects of tandem BET BD inhibition both in cancer models and, as we and others have reported of BRDT, in the testes. To find novel BET BD1 binders, we screened >4.5 billion molecules from our DNA-encoded chemical libraries with BRDT-BD1 or BRDT-BD2 proteins in parallel. A compound series enriched only by BRDT-BD1 was resynthesized off-DNA, uncovering a potent chiral compound, CDD-724, with >2,000-fold selectivity for inhibiting BRDT-BD1 over BRDT-BD2. CDD-724 stereoisomers exhibited remarkable differences in inhibiting BRDT-BD1, with the R-enantiomer (CDD-787) being 50-fold more potent than the S-enantiomer (CDD-786). From structure–activity relationship studies, we produced CDD-956, which maintained picomolar BET BD1 binding potency and high selectivity over BET BD2 proteins and had improved stability in human liver microsomes over CDD-787. BROMOscan profiling confirmed the excellent pan-BET BD1 affinity and selectivity of CDD-787 and CDD-956 on BD1 versus BD2 and all other BD-containing proteins. A cocrystal structure of BRDT-BD1 bound with CDD-956 was determined at 1.82 Å and revealed BRDT-BD1–specific contacts with the αZ and αC helices that explain the high affinity and selectivity for BET BD1 versus BD2. CDD-787 and CDD-956 maintain cellular BD1-selectivity in NanoBRET assays and show potent antileukemic activity in acute myeloid leukemia cell lines. These BET BD1-specific and highly potent compounds are structurally unique and provide insight into the importance of chirality to achieve BET specificity.
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