Ningetinib tosylate is an inhibitor of tyrosine kinase inhibitor (TKI) and the IC50 for c-Met, VEGFR2 and Axl are 6.7 nM, 1.9 nM and <1.0 nM respectively.
Ningetinib Tosylate is the tosylate salt form of Ningetinib. Ningetinib is a potent and multiple-target tyrosine kinase inhibitor with IC50 values of 6.7, 1.9 and < 1.0 nM against c-Met, VEGFR-2 and Axl, as well as tyrosine kinase Mer, and FLT3, all of which have been implicated in tumor pathogenesis. Ningetinib exhibited inhibition of HGF and VEGF-stimulated HUVEC proliferation and microvascular angiogenesis in rat aortic rings with IC50 values of 8.6 and 6.3 nM, respectively. Ningetinib showed good pharmacodynamics as a single oral dose of 3mg/kg Ningetinib potently inhibited the phosphorylation of c-Met and its downstream signaling kinases AKT and ERK1/2 for up to 6 hours in tumor tissues of U87MG tumor-bearing nude mice. Also it displayed excellent oral bioavailability (> 60% across animal species). Ningetinib exhibited antitumor efficacy in various human tumor subcutaneous xenograft models in athymic mice, including Caki-1 (kidney carcinoma), U-87MG (glioblastoma), NCI-H441 (lung adenocarcinoma), MDA-MB-231 (breast adenocarcinoma), SMMC-7721 (hepatoma), 5637 (bladder carcinoma) and SK-OV-3 (ovarian carcinoma), with ED50 values ranging in < 1mg/kg (NCI-H441) to ∼ 6 mg/kg (SMMC-7721). It prolonged the median survival time and yielded significant increase in life-span value (ILS = 32%, p = 0.003) at an oral dose of 20 mg/kg/day (dosed 21 days) in orthotopic U87MG human glioblastoma xenograft model versus the vehicle-treated group[1]. Up to now, a phase I/II study of ningetinib to treat for non-small cell lung cancer, and a phase I to renal cancer and acute myeloid leukaemia are under recruiting (https://clinicaltrials.gov/).
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