Initial solid tumor testing (Stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program

作者: Peter J Houghton , Raushan T Kurmasheva , Dmitry Lyalin , John M Maris , E Anders Kolb

DOI: 10.1002/PBC.25175

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摘要: Background AZD1480 is an ATP competitive inhibitor of Janus kinases 1 and 2 (JAK1, 2) that has been shown to inhibit the growth solid tumor models. This agent was selected for testing putative role JAK/STAT signaling in standard PPTP models. Procedures AZD1480 tested against vitro cell line panel at concentrations from 1.0 nM 10 μM vivo xenograft panels (60 mg/kg once daily (SID) × 5) three consecutive weeks. Additional studies evaluated 5 20 mg/kg BID × 5 with SID dosing 7–30 mg/kg weekends weeks. Results In median relative IC50 (rIC50) lines 1.5 µM, a range 0.3 µM 5.9 µM. The two rIC50 values both had ALK activating genomic alterations. AZD1480 demonstrated statistically significant differences (P   2) or high-level inhibition 15 30 (50%) xenografts. Tumor regressions were observed six Wilms models doses induced Stat3(Y705) phosphorylation. Conclusions AZD1480 most xenografts, similar antiangiogenic agents by PPTP. regressing activity noted Pediatr Blood Cancer 2014;61:1972–1979. © 2014 Wiley Periodicals, Inc.

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