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|Section2= |Section3= }} Crenolanib besylate (CP-868,596-26; 4-piperidinamine, 1-- 8-quinolinyl]-, monobenzenesulfonate) is an investigational inhibitor being developed by AROG Pharmaceuticals, LLC. The compound is currently being evaluated for safety and efficacy in clinical trials for various types of cancer, including acute myeloid leukemia (AML), gastrointestinal stromal tumor (GIST), and glioma. Crenolanib is an orally bioavailable benzamidazole that selectively and potently inhibits signaling of wild-type and mutant isoforms of class III receptor tyrosine kinases (RTK) FLT3 (FMS-like Tyrosine Kinase 3), PDGFR α (Platelet-Derived Growth Factor Receptor), and PDGFR β. Unlike most RTK inhibitors, crenolanib is a type I mutant-specific inhibitor that preferentially binds to phosphorylated active kinases with the ‘DFG in’ conformation motif. == Background == Type III Receptor tyrosine kinase, including FLT3, PDGFRα and PDGFRβ, have been directly implicated in the pathogenesis of epithelial, mesenchymal, and hematological malignancies. Mutations of FLT3 comprise one of the most frequently identified types of genetic alterations in Angiomyolipoma. Approximately one-third of AML patients present with a mutation in this gene.〔 The majority of these mutations result in constitutive activation of downstream signaling pathways and aberrant cell growth.〔 Mutations in FLT3 have also been reported in acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). Activating mutations in PDGFRA have been detected in 5-12% of Gastrointestinal stromal tumor. Fusion of PDGFRA has been found to be responsible for hematological malignances like hypereosinophilic syndrome. The amplification of chromosome 4q12, the site of the PDGFRA gene, has been identified in 13-29% of adult gliomas and in 29% to 36% of diffuse intrinsic pontine gliomas (DIPG), a subset of high-grade gliomas (HGG) in pediatric patients. Activation of PDGFRB, a third member of the type III RTK family, has been implicated in the development of chronic myelomonocytic leukemia due to the fusion of PDGFRB with the TEL gene.〔 Furthermore, PDGFB translocation to the COL1A1 gene locus has been identified to be responsible for dermatofibrosarcoma protuberans (DFSP).〔 In cancer cells, PDGFR promotes tumor development and migration via proto-oncogenic downstream mediators like AKT and MEK. In stromal fibroblasts, PDGFRα activation leads to local tissue invasion, production and secretion of VEGF, and elevated intratumoral interstitial pressure. In stromal pericytes, PDGFRβ activation mediates vascular stability.〔 Thus, either FLT3 or PDGF/PDGFR pathway is the primary driver of oncogenesis in the above malignancies and can be targeted by crenolanib therapy. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Crenolanib」の詳細全文を読む スポンサード リンク
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