ArticleMolecular cancer therapeutics2008
Z3, a novel Jak2 tyrosine kinase small-molecule inhibitor that suppresses Jak2-mediated pathologic cell growth.
Article in Molecular cancer therapeutics, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 25 citations in OpenAlex.
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Detection of Exon 12 and 14 Mutations in Janus Kinase 2 Gene Including a Novel Mutant in V617F Negative Polycythemia Vera Patients from Pakistan.Journal of Cancer · 2018Article
- Hexim1, a Novel Regulator of Leptin Function, Modulates Obesity and Glucose Disposal.Molecular endocrinology (Baltimore, Md.) · 2016Article
- Everolimus-induced human keratinocytes toxicity is mediated by STAT3 inhibition.Journal of experimental & clinical cancer research : CR · 2013Article
- A46, a benzothiophene-derived compound, suppresses Jak2-mediated pathologic cell growth.Experimental hematology · 2012Article
- The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo.The Journal of biological chemistry · 2011Article
- A structure-function perspective of Jak2 mutations and implications for alternate drug design strategies: the road not taken.Current medicinal chemistry · 2011Review
- The constitutive activation of Jak2-V617F is mediated by a π stacking mechanism involving phenylalanines 595 and 617.Biochemistry · 2010Article
- Article
- Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases.Journal of cellular and molecular medicine · 2010Review
- Identifying druggable disease-modifying gene products.Current opinion in chemical biology · 2009Review
- Identification of a novel inhibitor of JAK2 tyrosine kinase by structure-based virtual screening.Bioorganic & medicinal chemistry letters · 2009Article
- Prospect of JAK2 inhibitor therapy in myeloproliferative neoplasms.Expert review of anticancer therapy · 2009Review
- Jak2 inhibitors: rationale and role as therapeutic agents in hematologic malignancies.Current oncology reports · 2009Review
- Novel strategies for patients with chronic myeloproliferative disorders.Current opinion in hematology · 2009Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Jak2 tyrosine kinase is essential for animal development and hyperkinetic Jak2 function has been linked to a host of human diseases. Control of this pathway using Jak2-specific inhibitors would therefore potentially serve as a useful research tool and/or therapeutic agent. Here, we used a high-throughput program called DOCK to predict the ability of 20,000 small molecules to interact with a structural pocket adjacent to the ATP-binding site of murine Jak2. One small molecule, 2-methyl-1-phenyl-4-pyridin-2-yl-2-(2-pyridin-2-ylethyl)butan-1-one (herein designated as Z3), bound to Jak2 with a favorable energy score. Z3 inhibited Jak2-V617F and Jak2-WT autophosphorylation in a dose-dependent manner but was not cytotoxic to cells at concentrations that inhibited kinase activity. Z3 selectively inhibited Jak2 kinase function with no effect on Tyk2 or c-Src kinase function. Z3 significantly inhibited proliferation of the Jak2-V617F-expressing, human erythroleukemia cell line, HEL 92.1.7. The Z3-mediated reduction in cell proliferation correlated with reduced Jak2 and STAT3 tyrosine phosphorylation levels as well as marked cell cycle arrest. Finally, Z3 inhibited the growth of hematopoietic progenitor cells isolated from the bone marrow of an essential thrombocythemia patient harboring the Jak2-V617F mutation and a polycythemia vera patient carrying a Jak2-F537I mutation. Collectively, the data suggest that Z3 is a novel specific inhibitor of Jak2 tyrosine kinase.
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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.