Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various growth factor receptors contain intrinsic tyrosine kinase activity, indicating that protein tyrosine kinases (PTK) play an important role in signal transduction pathways for cell proliferation and differentiation. To identify oocyte-derived factors which control follicle cells as well as oocyte-controlling factors produced by follicle cells, we examined the expression of genes which contain the PTK domain in the porcine ovary, using a polymerase chain reaction-based amplification technique with degenerate oligonucleotide primers that are specific to the PTK domain. Clones for the porcine homologues of platelet-derived growth factor receptor alpha (PDGFRalpha) and of insulin-like growth factor-I receptor (IGF-IR) were found during follicle growth both in oocytes and follicle cells. Clones for the porcine homologues of focal adhesion kinase (FAK), of c-kit and of fms-like tyrosine kinase (FLT)-3 were found only in oocytes. Moreover, after 24 h of in-vitro maturation of the cumulus-oocyte complexes, clones for the porcine homologues of FLT-1, of FLT-4, of Tie2 and of RYK in oocytes were observed. Immunohistochemical studies revealed the existence of PDGFRalpha, platelet-derived growth factor A (PDGFA), FAK and FLT3 in oocytes at various stages of folliculogenesis. These results suggest that fluctuations in the expression of these PTK genes may be involved in follicle growth and maturation.
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PMID:Protein tyrosine kinase expression in the porcine ovary. 1147 Aug 59

Imatinib mesylate, also known as STI571 or CGP57148, is a competitive inhibitor of a few tyrosine kinases, including BCR-ABL, ABL, KIT, and the platelet-derived growth factor receptors (PDGF-R). It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 300 mg or greater, the vast majority of patients with chronic myeloid leukaemia achieve a haematological response and this is usually associated with limited toxicity. Imatinib also has substantial activity in Philadelphia chromosome-positive acute lymphoblastic leukaemia expressing the BCR-ABL fusion protein. Gastrointestinal stromal tumours (GISTs) have also been evaluated for clinical activity of imatinib. About 90% of malignant GISTs harbour a mutation in c-kit leading to KIT receptor autophosphorylation and ligand-independent activation. According to initial clinical studies, more than 50% of GISTs respond to therapy within a few months, and only about 10-15% progress. The potential for cure and the optimal length of treatment are currently not known. Several other human cancers may over-express KIT or PDGF-R, and clinical trials to evaluate the role of imatinib in the treatment of such cancers are currently ongoing. Imatinib is an example of a specifically designed, highly targeted cancer therapy, which poses novel requirements for both pathology laboratories and clinicians in terms of identifying the major molecular mechanisms involved in tumour growth.
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PMID:Tyrosine kinase inhibitor imatinib (STI571) as an anticancer agent for solid tumours. 1168 Jul 92

The proto-oncogene c-kit encodes a transmembrane receptor with tyrosine kinase activity, which transduces signal from kit ligand (KL), and is responsible for hematogenesis, melanogenesis and gametogenesis during fetal development and adult life. Partial or complete loss of c-kit function due to mutation of the c-kit or KL gene accounts for the phenotypes of the murine White-spotting and Steel mutations, respectively. The c-kit protein has the structural features of extracellular immunoglobulin-like domains and intracellular kinase domain with a hydrophilic 'insert'. These features have categorized c-kit along with platelet-derived growth factor receptors, colony-stimulating factor 1 receptor (c-fms) and others to subclass III of the receptor tyrosine kinases. We report the structure of the murine c-kit gene. The c-kit gene consists of 21 exons and spans at least 70 kb. The 5' and 3' flanking exons encode the untranslated sequences as well as part of the coding sequence. The internal exons are typically small with each of them encoding a structurally important subunit of the protein. Comparison of gene structures of members of the subclass III receptor tyrosine kinases has improved our understanding of the structure-functional relationship of the c-kit protein. Copyright 1995 S. Karger AG, Basel
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PMID:The Genomic Structure of the Proto-Oncogene c-kit Encoded at the Murine White Spotting Locus. 1172 39

Angiogenesis plays a critical role in the growth and metastasis of solid and hematologic malignancies. This complex and highly regulated process involves numerous different cell types and mediators. Vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor are among the soluble factors that stimulate this process. They are ligands for specific tyrosine kinase receptors that are important in transduction of intracellular signals and induction of angiogenesis. SU6668 is a novel molecule that competitively inhibits the tyrosine kinase of the receptors for vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, and c-kit. In vitro studies have confirmed that SU6668 inhibits growth factor-stimulated tyrosine phosphorylation. SU6668 also has significant antitumor activity against many types of tumor xenograft explants in athymic mice. SU6668 inhibits angiogenesis through several mechanisms, including the induction of apoptosis in vascular endothelial cells and tumor cells. Currently, Phase 1 studies are being initiated to evaluate the potential of SU6668 as an anticancer agent for humans.
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PMID:SU6668, a multitargeted angiogenesis inhibitor. 1177 84

Mastocytosis is a rare stem cell disorder characterized by abnormal growth and accumulation of mast cells in one or more organ systems. Clinical heterogeneity is a hallmark of mastocytosis. Recent observations of activating mutations in c-kit may help to understand the abnormal growth of mast cells in mastocytosis. However, this mutation alone does not explain the entire clinical heterogeneity of the disease. Reticulin fibrosis is also commonly associated with systemic mastocytosis. Mast cells are known to be the source of fibrogenic cytokines, including platelet-derived growth factor, transforming growth factor-beta (TGF beta) and basic fibroblast growth factor (bFGF). Immunohistochemical studies show a close correlation between the mast cell expression of bFGF and the reticulin fibrosis of mastocytosis lesions. The study of cytokine receptor expression also demonstrates that the TGF beta receptor I (RI)-negative cases of mastocytosis are prognostically less favorable than the TGF beta RI-positive cases. This finding may be related to the fact that the TGF beta R complex functions as a tumor suppressor gene in neoplastic cells.
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PMID:Mastocytosis and fibrosis: role of cytokines. 1191 21

Imatinib is a potent drug used in treatment of chronic myeloid leukaemia (CML). It acts by inhibition of the CML-specific p210 BCR-ABL tyrosine kinase, but also blocks other pathways such as platelet-derived growth factor (PDGF) and c-kit receptor signalling. Clinical trials have confirmed the efficacy of imatinib, which has toxic effects in cells that express BCR-ABL. Side-effects, although frequent, are generally mild and include superficial oedema and fluid retention. Here, we describe two patients with cerebral oedema, which in one patient was fatal. The pathophysiological mechanisms remain unknown, although the drug could act through inhibition of the PDGF receptor.
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PMID:Cerebral oedema as a possible complication of treatment with imatinib. 1204 68

Aberrant expression and activating mutations of the class III receptor tyrosine kinase Flt3 (Flk-2, STK-1) have been linked to poor prognosis in acute myeloid leukemia (AML). Inhibitors of Flt3 tyrosine kinase activity are, therefore, of interest as potential therapeutic compounds. We previously described bis(1H-2-indolyl)-1-methanones as a novel class of selective inhibitors for platelet-derived growth factor receptors (PDGFR). Several bis(1H-2-indolyl)-1-methanone derivatives, represented by the compounds D-64406 and D-65476, are also potent inhibitors of Flt3. They inhibit proliferation of TEL-Flt3-transfected BA/F3 cells with IC(50) values of 0.2-0.3 microM in the absence of IL-3 but >10 microM in the presence of IL-3. Ligand-stimulated autophosphorylation of Flt3 in EOL-1 cells and corresponding downstream activation of Akt/PKB are effectively inhibited by bis(1H-2-indolyl)-1-methanones whereas autophosphorylation of c-Kit/SCF receptor or c-Fms/CSF-1 receptor is less sensitive or insensitive, respectively. Flt3 kinase purified by different methods is potently inhibited in vitro, demonstrating a direct mechanism of inhibition. 32D cells, expressing a constitutively active Flt3 variant with internal tandem duplication are greatly sensitized to radiation-induced apoptosis in the presence of D-64406 or D-65476 in the absence but not in the presence of IL-3. Thus, bis(1H-2-indolyl)-1-methanones are potential candidates for the treatment of Flt3-driven leukemias.
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PMID:Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. 1214 94

Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-molecular weight therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clinical trials). Three examples of inhibitors of protein kinases are reviewed, including low-molecular weight compounds targeting the cell cycle kinases; a potent and selective inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrollopyrimidine PKI166; and the 2-phenyl-aminopyrimidine STI571 (Glivec(R), Gleevec) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been found to be overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear association with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clinical utility of protein kinase inhibitors as therapeutic agents. In a preclinical model, STI571 (Glivec(R), Gleevec) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase I/II studies demonstrated that STI571 is well tolerated, and that it showed promising hematological and cytogenetic responses in CML and clinical responses in the c-Kit-driven gastrointestinal tumors.
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PMID:Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. 1219 2

Dermatofibrosarcoma protuberans (DFSP) is a rare superficial sarcoma usually affecting the trunk, with significant risk of local recurrence. It is characterized by the presence of ring chromosomes or chromosomal translocations fusing the promoter of the collagen gene COL1A1 to the platelet-derived growth factor beta-chain gene PDGFB, increasing the production of PDGF locally and promoting autocrine or paracrine tumor growth. Fewer than 5% of patients with DFSP develop metastatic sarcoma, with a poor subsequent prognosis. Imatinib (STI-571) was developed as an inhibitor of the PDGF receptor tyrosine kinase and has proven clinical activity against chronic myelogenous leukemia (expressing bcr-abl) and gastrointestinal stromal tumors (expressing c-kit). We describe 2 patients with metastatic and unresectable metastases from DFSP treated with imatinib. After confirmation of negative CD117 status of 2 sarcomas arising from DFSP, patients were given imatinib 400 mg po qd and assessed at regular intervals for their tolerance and response to therapy. One patient had a transient response, then progressed rapidly and died of disease. Another patient showed a partial response to therapy after 2 months, with resolution of superior vena cava syndrome and shrinking of metastatic lung lesions. His response is ongoing after 6 months of therapy. These clinical data confirm findings from models of DFSP and support the use of imatinib in the rare setting of metastatic DFSP. Imatinib may be useful for patients with locally advanced DFSP, when other options for local therapy are limited.
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PMID:Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. 1220 98

The tyrosine kinase inhibitor STI-571 potently blocks BCR-Abl, platelet-derived growth factor (PDGF) alpha- and beta-receptors, and c-Kit kinase activity. Flt3, a receptor tyrosine kinase closely related to PDGF receptors and c-Kit is, however, not inhibited by STI-571. Sequence alignments of different kinases and indications from the crystal structure of the STI-571 Abl kinase complex revealed amino acid residues that are probably crucial for this activity profile. It was predicted that Flt3 Phe-691 in the beta5 strand may sterically prevent interaction with STI-571. The point mutants Flt3 F691T and PDGFbeta-receptor T681F were constructed, and kinase assays showed that the Flt3 mutant but not the PDGFbeta-receptor mutant is inhibited by STI-571. Docking of STI-571 into computer models of the PDGFbeta-receptor and Flt3 kinase domains and comparison with the crystal structure of the STI-571 Abl kinase complex indicated very similar binding sites among the three nonphosphorylated kinases, suggesting corresponding courses of their Asp-Phe-Gly motifs and activation loops. Accordingly, we observed reduced sensitivity of preactivated compared with nonactivated PDGFR-beta for the inhibition by STI-571. Courses of the activation loop that collide with STI-571 binding explain its inactivity at other kinases as the insulin receptor. The binding site models of PDGFR-beta and Flt3 were applied to predict structural approaches for more selective PDGFbeta-receptor inhibitors.
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PMID:A single amino acid exchange inverts susceptibility of related receptor tyrosine kinases for the ATP site inhibitor STI-571. 1243 30


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