CP-673451 is a selective inhibitor of PDGFRα/β with IC50 of 10 nM/1 nM in cell-free assays, exhibits > 450-fold selectivity over other angiogenic receptors, has antiangiogenic and antitumor activity.
The activating mutations of KIT or PDGFRα are important to the pathogenesis of tumors. CP-673451 is a potent and selective inhibitor of PDGFRα and PDGFRβ with IC50 values of 10nM and 1nM, respectively, with more than 250-fold selectivity for PDGFRβthan c-kit kinase, 450-5000 fold than other angiogenic tyrosine kinases, including VEGFR-1, VEGFR-2, TIE-2 and FGFR-2 (measured by kinase inhibition assay). Treatment with CP-673451 at concentration of 3-100nM caused dose-dependent inhibition of p-PDGFR induced by PDGF-BB with IC50 value of 6.4nM in PAE-PDGFR-βcells. Oral dose of 3, 10 and 30mg/kg CP-673451 daily for 5 days inhibited PDGF-BB-induced angiogenesis by 70%, 81% and 95% in the sponge model, with no obvious inhibition of bFGF-and VEGF165-induced antiangiogenesis at dose of 5mg/kg. Dose-dependent decrease of p-PDGFR by CP-673451 can be observed in C6 tumors treated with CP-673451 at 33mg/kg and 100mg/kg in ex vivo study. Oral treatment with CP-673451 q.d. or b.i.d. for 10-11 days caused tumor growth inhibition in U87MG xenografts by 80% at dose of 100mg/kg, LS174T xenografts by 64% at 50mg/kg, H460 xenografts by 80% at 33mg/kg and Colo205 xenografts by 75% at 33mg/kg. Reduction of microvascular density up to 47% can be observed in tumors of Colo205-bearing mice dosed with 5mg/kg CP-673451 twice daily for 5 days. Combination of 33mg/kg CP-673451 once daily for 10 days with 10mg/kg Paclitaxel dosed once daily on days 1 to 5 caused tumor growth inhibition by 88%, compared with the agent alone by 49% or 54%, in mice bearing LS174T human colon adenocarcinoma xenografts[1].
作用机制
CP-673451 is an ATP-competitive inhibitor of PDGFR.[1]
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