Pz-1

Pz-1 is a potent RET and VEGFR2 inhibitor with IC₅₀s of less than 1 nM for both wild type kinases. IC50 & Target: IC50: < 1 nM (RET and VEGFR2)^[1] In Vitro: Pz-1 is a Type-II tyrosine kinase inhibitor, able to bind the DFG-out conformation of the kinase. In cell-based assays, 1.0 nM of Pz-1 strongly inhibits tyrosine phosphorylation of VEGFR2 and clinically relevant RET mutants, including those refractory to vandetanib and cabozantinib (RET^V804M and RET^V804L)^[1]. In Vivo: Pz-1 is shown active on VEGFR2, which can block blood supply required for RET-stimulated growth. At 1.0 mg/kg/day per os, Pz-1 abrogates formation of tumors induced by RET-mutant fibroblasts and blocks phosphorylation of both RET and VEGFR2 in tumor tissue. Pz-1 features no detectable toxicity up to 100.0 mg/kg, which indicates a large therapeutic window^[1].