ArticleJournal of medicinal chemistry2014
Biased multicomponent reactions to develop novel bromodomain inhibitors.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed.
- Fragment-Based Discovery of BRD4-BD2 Selective Binders: Biophysical Validation and Structural Insights for Domain-Selective Inhibitor Design.ACS omega · 2026Article
- High-Risk Neuroblastoma Stage 4 (NBS4): Developing a Medicinal Chemistry Multi-Target Drug Approach.Molecules (Basel, Switzerland) · 2025Article
- Deciphering Selectivity Mechanism of BRD9 and TAF1(2) toward Inhibitors Based on Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations.Molecules (Basel, Switzerland) · 2023Article
- 'Chemistry at the speed of sound': automated 1536-well nanoscale synthesis of 16 scaffolds in parallel.Green chemistry : an international journal and green chemistry resource : GC · 2023Article
- Catalyst-Free, Room-Temperature Accessible Regioselective Synthesis of Spiroquinolines and Their Antioxidant Study.ACS omega · 2023Article
- FACT subunit SUPT16H associates with BRD4 and contributes to silencing of interferon signaling.Nucleic acids research · 2022Article
- One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles.Beilstein journal of organic chemistry · 2022Article
- Design and Synthesis of Hybrid Compounds as Epigenetic Modifiers.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Optimization of Naphthyridones into Selective TATA-Binding Protein Associated Factor 1 (TAF1) Bromodomain Inhibitors.ACS medicinal chemistry letters · 2021Article
- Structural modification of 4, 5-dihydro-[1, 2, 4] triazolo [4, 3-f] pteridine derivatives as BRD4 inhibitors using 2D/3D-QSAR and molecular docking analysis.Molecular diversity · 2021Article
- Bioactivation of Isoxazole-Containing Bromodomain and Extra-Terminal Domain (BET) Inhibitors.Metabolites · 2021Article
- Development of Dimethylisoxazole-Attached Imidazo[1,2-Journal of medicinal chemistry · 2021Article
- FACT subunit SUPT16H associates with BRD4 and contributes to silencing of antiviral interferon signaling.bioRxiv : the preprint server for biology · 2021Article
- Alkynoates as Versatile and Powerful Chemical Tools for the Rapid Assembly of Diverse Heterocycles under Transition-Metal Catalysis: Recent Developments and Challenges.Topics in current chemistry (Cham) · 2021Review
- Bromodomain and BET family proteins as epigenetic targets in cancer therapy: their degradation, present drugs, and possible PROTACs.RSC advances · 2020Review
- Synthesis of Biologically Active Molecules through Multicomponent Reactions.Molecules (Basel, Switzerland) · 2020Review
- The Groebke-Blackburn-Bienaymé Reaction.European journal of chemistry (Print) · 2019Article
- Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold.ACS medicinal chemistry letters · 2019Article
- Targeting Brd4 for cancer therapy: inhibitors and degraders.MedChemComm · 2018Review
- Chromatin dependencies in cancer and inflammation.Nature reviews. Molecular cell biology · 2018Review
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.
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