ArticleThe Journal of biological chemistry2013
FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
82 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Contemporary Molecular Biology of Sporadic Vestibular Schwannomas: A Systematic Review and Clinical Implications.The journal of international advanced otology · 2018Pooled it
- Double-Blind Phase III Randomized Trial of the Antiprogestin Agent Mifepristone in the Treatment of Unresectable Meningioma: SWOG S9005.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2015Trial
- Epigenomic characterization of locally advanced anal cancer: a radiation therapy oncology group 98-11 specimen study.Diseases of the colon and rectum · 2014Trial
- High-resolution CRISPR/Cas9 screens identify PAK2 as a suppressor of macrophage proliferation.bioRxiv : the preprint server for biology · 2026Article
- p21-Activated Kinase (PAK) Group I-Targeting Inhibitors Promote the Dimeric Conformation in Live Cells.ACS chemical biology · 2026Article
- Splicing-associated network PAK1-CLK1/4-SRRM1 is a vulnerability to overcome chemoresistance in human and mouse acute myeloid leukemia.Science translational medicine · 2026Article
- Rho GTPases in cancer resistance: mechanisms, vulnerabilities, and therapeutic opportunities.Biochemical Society transactions · 2026Review
- NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress.The Journal of clinical investigation · 2026Article
- Rac/Cdc42 inhibitors target pancreatic cancer cells and macrophages in the tumor microenvironment.Cancer treatment and research communications · 2026Article
- PAK2 promotes CTC cluster formation by phosphorylating E-cadherin to enhance cell-cell adhesion in breast cancer.Breast cancer research : BCR · 2025Article
- Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization.Current issues in molecular biology · 2025Article
- Discovery of a Novel Selective PAK1/HDAC6/HDAC10 Inhibitor ZMF-25 that Induces Mitochondrial Metabolic Breakdown and Autophagy-Related Cell Death in Triple-Negative Breast Cancer.Research (Washington, D.C.) · 2025Article
- Regulation of Cancer Metastasis by PAK2.International journal of molecular sciences · 2024Review
- Regulation of Vascular Injury and Repair by P21-Activated Kinase 1 and P21-Activated Kinase 2: Therapeutic Potential and Challenges.Biomolecules · 2024Review
- Rac1 GTPase Regulates the βTrCP-Mediated Proteolysis of YAP Independently of the LATS1/2 Kinases.Cancers · 2024Article
- Synergistic effects of combined BET and FAK inhibition against Vestibular Schwannomas in NF2-related Schwannomatosis.Oncogene · 2024Article
- PAK3 activation promotes the tangential to radial migration switch of cortical interneurons by increasing leading process dynamics and disrupting cell polarity.Molecular psychiatry · 2024Article
- Targeting SMAD-Dependent Signaling: Considerations in Epithelial and Mesenchymal Solid Tumors.Pharmaceuticals (Basel, Switzerland) · 2024Review
- A novel pipeline for prioritizing cancer type-specific therapeutic vulnerabilities using DepMap identifies PAK2 as a target in head and neck squamous cell carcinomas.Molecular oncology · 2024Article
- PAK inhibitor FRAX486 decreases the metastatic potential of triple-negative breast cancer cells by blocking autophagy.British journal of cancer · 2024Article
22 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
The p21-activated kinases (PAKs) are immediate downstream effectors of the Rac/Cdc42 small G-proteins and implicated in promoting tumorigenesis in various types of cancer including breast and lung carcinomas. Recent studies have established a requirement for the PAKs in the pathogenesis of Neurofibromatosis type 2 (NF2), a dominantly inherited cancer disorder caused by mutations at the NF2 gene locus. Merlin, the protein product of the NF2 gene, has been shown to negatively regulate signaling through the PAKs and the tumor suppressive functions of Merlin are mediated, at least in part, through inhibition of the PAKs. Knockdown of PAK1 and PAK2 expression, through RNAi-based approaches, impairs the proliferation of NF2-null schwannoma cells in culture and inhibits their ability to form tumors in vivo. These data implicate the PAKs as potential therapeutic targets. High-throughput screening of a library of small molecules combined with a structure-activity relationship approach resulted in the identification of FRAX597, a small-molecule pyridopyrimidinone, as a potent inhibitor of the group I PAKs. Crystallographic characterization of the FRAX597/PAK1 complex identifies a phenyl ring that traverses the gatekeeper residue and positions the thiazole in the back cavity of the ATP binding site, a site rarely targeted by kinase inhibitors. FRAX597 inhibits the proliferation of NF2-deficient schwannoma cells in culture and displayed potent anti-tumor activity in vivo, impairing schwannoma development in an orthotopic model of NF2. These studies identify a novel class of orally available ATP-competitive Group I PAK inhibitors with significant potential for the treatment of NF2 and other cancers.
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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.