ArticleJournal of molecular biology2009
PAC-1 activates procaspase-3 in vitro through relief of zinc-mediated inhibition.
Article in Journal of molecular biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 166 citations in OpenAlex.
- A clinical-stage oncology compound selectively targets drug-resistant cancers.bioRxiv : the preprint server for biology · 2026Article
- Blocking XIAP:CASP7-p19 selectively induces apoptosis of CASP3/DR malignancies by a novel reversible small molecule.Cell death & disease · 2025Article
- PAC-1 Synergizes with Sunitinib to Enhance Cell Death in Pancreatic Neuroendocrine Tumors.ACS pharmacology & translational science · 2025Article
- Decoding the Implications of Zinc in the Development and Therapy of Leukemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Artificial intelligence analysis applied to the treatment of granulosa cell tumors of the ovary.Frontiers in artificial intelligence · 2025Article
- PI3K-AKT-mediated phosphorylation of Thr260 in CgCaspase-3/6/7 regulates heat-induced activation in oysters.Communications biology · 2024Article
- Research on the Action and Mechanism of Pharmacological Components ofInternational journal of molecular sciences · 2024Review
- ONC212, alone or in synergistic conjunction with Navitoclax (ABT-263), promotes cancer cell apoptosis via unconventional mitochondrial-independent caspase-3 activation.Cell communication and signaling : CCS · 2024Article
- Raptinal: a powerful tool for rapid induction of apoptotic cell death.Cell death discovery · 2024Review
- Synthesis and Characterization of New N-acyl Hydrazone Derivatives of Carprofen as Potential Tuberculostatic Agents.Antibiotics (Basel, Switzerland) · 2024Article
- Article
- Inferring circRNA-drug sensitivity associations via dual hierarchical attention networks and multiple kernel fusion.BMC genomics · 2023Article
- Regulation of Peptidase Activity beyond the Active Site in Human Health and Disease.International journal of molecular sciences · 2023Review
- The evolution of small molecule enzyme activators.RSC medicinal chemistry · 2023Review
- Caspase 3 exhibits a yeast metacaspase proteostasis function that protects mitochondria from toxic TDP43 aggregates.Microbial cell (Graz, Austria) · 2023Article
- Article
- Phase I study of procaspase-activating compound-1 (PAC-1) in the treatment of advanced malignancies.British journal of cancer · 2023Article
- ARHGAP15 promotes metastatic colonization in gastric cancer by suppressing RAC1-ROS pathway.PLoS genetics · 2023Article
- Impact of cytotoxic agents or apoptosis stimulants on αklotho in MDCK, NRK-52E and HK2 kidney cells.Aging · 2022Article
- Design, synthesis and evaluation of novel 2-oxoindoline-based acetohydrazides as antitumor agents.Scientific reports · 2022Article
26 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
The direct induction of apoptosis has emerged as a powerful anticancer strategy, and small molecules that either inhibit or activate certain proteins in the apoptotic pathway have great potential as novel chemotherapeutic agents. Central to apoptosis is the activation of the zymogen procaspase-3 to caspase-3. Caspase-3 is the key "executioner" caspase, catalyzing the hydrolysis of a multitude of protein substrates within the cell. Interestingly, procaspase-3 levels are often elevated in cancer cells, suggesting a compound that directly stimulates the activation of procaspase-3 to caspase-3 could selectively induce apoptosis in cancer cells. We recently reported the discovery of a compound, PAC-1, which enhances procaspase-3 activity in vitro and induces apoptotic death in cancer cells in culture and in mouse xenograft models. Described herein is the mechanism by which PAC-1 activates procaspase-3 in vitro. We show that zinc inhibits the enzymatic activity of procaspase-3 and that PAC-1 strongly activates procaspase-3 in buffers that contain zinc. PAC-1 and zinc form a tight complex with one another, with a dissociation constant of approximately 42 nM. The combined data indicate that PAC-1 activates procaspase-3 in vitro by sequestering inhibitory zinc ions, thus allowing procaspase-3 to autoactivate itself to caspase-3. The small-molecule-mediated activation of procaspases has great therapeutic potential and thus this discovery of the in vitro mechanism of action of PAC-1 is critical to the development and optimization of other procaspase-activating compounds.
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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.