Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors.
By E. Buchdunger, C. Cioffi, N. M. Law, D. Stover, Sayuri Ohno-Jones, Brian J. Druker, N. Lydon. Journal of Pharmacology and Experimental Therapeutics, 2000
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STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase inhibitor that is currently in clinical trials for the treatment of chronic myelogenous leukemia. STI571 selectively inhibits the Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and blocks cellular proliferation and tumor growth of Bcr-abl- or v-abl-expressing cells. We have further investigated the profile of STI571 against related receptor tyrosine kinases. STI571 was found to potently inhibit the kinase activity of the alpha- and beta-PDGF receptors and the receptor for stem cell factor, but not the closely related c-Fms, Flt-3, Kdr, Flt-1, and Tek tyrosine kinases. Additionally, no inhibition of c-Met or nonreceptor tyrosine kinases such as Src and Jak-2 has been observed. In cell-based assays, STI571 selectively inhibited PDGF and stem cell factor-mediated cellular signaling, including ligand-stimulated receptor autophosphorylation, inositol phosphate formation, and mitogen-activated protein kinase activation and proliferation. These results expand the profile of STI571 and suggest that in addition to chronic myelogenous leukemia, STI571 may have clinical potential in the treatment of diseases that involve abnormal activation of c-Kit or PDGF receptor tyrosine kinases.
Subfields: Genetics, Hematology, Immunology
View Paper: https://www.semanticscholar.org/paper/ef137647f2e0268cc93674e1c30a2a52aed458b3
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Citations in the corpus
- Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. (2005, background): “…tyrosine kinase activity of Bcr-Abl and of the c-Kit and PDGF receptors, has proven to be an effective treatment for CML- and c-Kitpositive gastrointestinal stromal tumors (GISTs) (Buchdunger et al., 1996; Druker et al., 1996; Carroll et al., 1996; Buchdunger et al., 2000; Demetri et al., 2002).”
- Evolution of Cancer Pharmacological Treatments at the Turn of the Third Millennium (2018, background): “Several clinical trials have demonstrated the efficacy and safety of Imatinib in patients affected by CML, ALL, and GIST.”
- Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. (2003, background): “tently inhibited by imatinib (IC50, 100 to 200 nmol/L), consistent with earlier reports.(12) Imatinib was similarly effective against the V561D, del DIMH842–845, and delI843 PDGFRA isoforms”
- The target landscape of clinical kinase drugs (2017, background): “The discovery that the BCR-ABL inhibitor imatinib also potently inhibits c-KIT and platelet-derived growth factor receptor (PDGFR) mutations extended the use of this drug from chronic myelogenous leukemia to the treatment of gastrointestinal stroma tumors (47).”
- Risk stratification of patients diagnosed with gastrointestinal stromal tumor. (2008, background): “PDGFRA mutations, most commonly represented by the D842V point mutation, were not significantly associated with prognosis, although they tended to be associated with epithelioid morphology and low mitotic rates.”