The activating mutations of KIT or PDGFRα are important to the pathogenesis of tumors. Crenolanib is a potent class III RTKs inhibitor with Kd values of 3.2nM, 2.1nM and 0.74nM for PDGFRα, PDGFRβ and FLT3 (measured by Kd ELECT screening service), respectively, as well as showed kinase inhibition effect on imatinib-resistant mutation including PDGFRA D842I, D842V, D842Y and DI842-843IM in CHO cells transfected with PDGFRA constructs. Consistent with this, Crenolanib inhibited cell proliferation more potently than imatinib in BaF3 expressed PDGFRA-D842V mutation cells at concentration>50nM[1]. As the potent inhibition by Crenolanib to FLT3, Crenolanib at concentration ranging in 1-50nM dose-dependently inhibited FLT3-ITD AML cell viability and FLT3 signaling, shown as decreased phosphorylation of –FLT3, STAT5, ERK and S6, in MV4-11 and MOLM-13 cells. Administration of Crenolanib at dose of 15mg/kg twice daily (Monday to Friday) for 3 consecutive weeks significantly reduced MOLM-13-RES-luc leukemic infiltration and produce a significant increase in survival in NSG mice engrafted with MOLM-13-RES-luc cells[2].
作用机制
Crenolanib is an selective ATP-competitive inhibitor of class III RTKs, PDGFRα, PDGFRβ and FLT3.[3]
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