ArticleStructure (London, England : 1993)2023
Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome.
Article in Structure (London, England : 1993), 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 43 citations in OpenAlex.
- Targeting ClpP Protease: Emerging Therapeutic Strategies and Small-Molecule Modulators in Drug Discovery.Medicinal research reviews · 2026Review
- Small molecule activators of the mitochondrial protease ClpP induce senescence in triple-negative breast cancer cells and sensitize cells to the Bcl-2 inhibitor venetoclax.Cell death & disease · 2026Article
- TANGO: direct optimization of constrained synthesizability for generative molecular design.Nature computational science · 2026Article
- Discovery of a pyridine-piperazine-based small molecule that enhances the activity of peptidase neurolysin.The Journal of pharmacology and experimental therapeutics · 2026Article
- Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.Nature communications · 2026Article
- Dysregulation of human ClpP using small molecules with piperazine-based scaffold for diffuse intrinsic pontine glioma therapy validated by patient-derived tumor organoids.Research square · 2026Article
- The role of dordaviprone in the multidisciplinary management of diffuse midline glioma.Surgical neurology international · 2026Review
- Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax.Research square · 2025Article
- Targeting the Mitochondrial Protease ClpP for Anticancer Therapy.Journal of medicinal chemistry · 2025Article
- Recent advances in the design of small molecules targeting human ClpP.Future medicinal chemistry · 2025Review
- Dose Optimization of ClpP Agonists Using an In Vitro Microfluidic Perfusion Platform and In Silico Pharmacokinetic-Pharmacodynamic Modeling.The AAPS journal · 2025Article
- Mechanism of allosteric activation in human mitochondrial ClpP protease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Dynamic Oligomerization Processes ofACS omega · 2025Article
- Epigenetic Threads of Neurodegeneration: TFAM's Intricate Role in Mitochondrial Transcription.CNS & neurological disorders drug targets · 2025Review
- Structure-guided development of selective caseinolytic protease P agonists as antistaphylococcal agents.Cell reports. Medicine · 2024Article
- Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201.International journal of molecular sciences · 2024Article
- Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.bioRxiv : the preprint server for biology · 2024Article
- Combining the constitutive TRAIL-secreting induced neural stem cell therapy with the novel anti-cancer drug TR-107 in glioblastoma.Molecular therapy. Oncology · 2024Article
- Review
- A review of current therapeutics targeting the mitochondrial protease ClpP in diffuse midline glioma, H3 K27-altered.Neuro-oncology · 2024Review
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Authors and funding
16 authors at 4 institutions in 3 countries.
Funding
Abstract
The mitochondrial ClpP protease is responsible for mitochondrial protein quality control through specific degradation of proteins involved in several metabolic processes. ClpP overexpression is also required in many cancer cells to eliminate reactive oxygen species (ROS)-damaged proteins and to sustain oncogenesis. Targeting ClpP to dysregulate its function using small-molecule agonists is a recent strategy in cancer therapy. Here, we synthesized imipridone-derived compounds and related chemicals, which we characterized using biochemical, biophysical, and cellular studies. Using X-ray crystallography, we found that these compounds have enhanced binding affinities due to their greater shape and charge complementarity with the surface hydrophobic pockets of ClpP. N-terminome profiling of cancer cells upon treatment with one of these compounds revealed the global proteomic changes that arise and identified the structural motifs preferred for protein cleavage by compound-activated ClpP. Together, our studies provide the structural and molecular basis by which dysregulated ClpP affects cancer cell viability and proliferation.
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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.