ArticleEuropean journal of medicinal chemistry2023
Elucidation of novel TRAP1-Selective inhibitors that regulate mitochondrial processes.
Article in European journal of medicinal chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Coordinated regulation of the metaboproteome by Hsp90 chaperones controls metabolic plasticity.iScience · 2026Article
- Attempts to Achieve Targeted Covalent Inhibition of Hsp90β.Chemical biology & drug design · 2026Article
- Targeting HSP90 in cancer: advances in the development of inhibitors, mechanisms of action, and therapeutic applications.Molecular cancer · 2026Review
- SCMO: a deep learning model integrating the single-cell resolution TME ecosystem and multi-omics for survival prediction in CRC patients.Journal of translational medicine · 2026Article
- Optimization of an Hsp90β-selective inhibitor via exploration of the Hsp90 N-terminal ATP-binding pocket.European journal of medicinal chemistry · 2025Article
- Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer.Cancer letters · 2025Article
- Combination Strategies with HSP90 Inhibitors in Cancer Therapy: Mechanisms, Challenges, and Future Perspectives.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Anti-inflammatory activities of novel heat shock protein 90 isoform selective inhibitors in BV-2 microglial cells.Frontiers in molecular biosciences · 2024Article
- Enniatin A Analogues as Novel Hsp90 Inhibitors that Modulate Triple-Negative Breast Cancer.ACS medicinal chemistry letters · 2023Article
- Synthesis and Validation of the First Cell-Impermeable Hsp90α-Selective Inhibitors.ACS medicinal chemistry letters · 2023Article
- The development of cancers research based on mitochondrial heat shock protein 90.Frontiers in oncology · 2023Review
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Hsp90 isoform-selective inhibitors represent a new paradigm for novel anti-cancer drugs as each of the four isoforms have specific cellular localization, function, and client proteins. The mitochondrial isoform, TRAP1, is the least understood member of the Hsp90 family due to the lack of small molecule tools to study its biological function. Herein, we report novel TRAP1-selective inhibitors used to interrogate TRAP1's biological function along with co-crystal structures of such compounds bound to the N-terminus of TRAP1. Solution of the co-crystal structure allowed for a structure-based approach that resulted in compound 36, which is a 40 nM inhibitor with >250-fold TRAP1 selectivity over Grp94, the isoform with the highest structural similarity to TRAP1 within the N-terminal ATP binding site. Lead compounds 35 and 36 were found to selectively induce TRAP1 client protein degradation without inducing the heat shock response or disrupting Hsp90-cytosolic clients. They were also shown to inhibit OXPHOS, alter cellular metabolism towards glycolysis, disrupt TRAP1 tetramer stability, and disrupt the mitochondrial membrane potential.
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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 Socratic graph.