T-1101 tosylate is a Hec1/Nek2 (Highly expressed in cancer 1 / NIMA-related kinase 2) inhibitor with antitumor activity. T-1101 tosylate is inactive toward normal cells, kinases and hERG.
Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. T-1101 tosylate is a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has a potent in vitro antiproliferative activity with IC50 of 14.8-21.5 nM. T-1101 tosylate (1 μM; 3-24 hours) decreased the level of Nek2 in a time-dependent manner. And treatment with 1 µM T-1101 tosylate for 24 hours induced apoptosis. Moreover, T-1101 tosylate reduced amounts of cell-cycle related proteins cyclin A1, cyclin B1, and cyclin D1. It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7). Oral co-administration of T-1101 tosylate (2.5 mg/kg; p.o.; twice per day) halved the dose of sorafenib from 25 mg/kg to 12.5 mg/kg required to exhibit comparable in vivo activity towards Huh-7 xenografts. Further, T-1101 tosylate (2.5 mg/kg; p.o.; twice per day) showed significant in vivo activity in mice bearing various human cancer xenografts. Subsequent salt screening showed that T-1101 tosylate has good oral area under the curve (AUC) (62.5 μM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy[1].
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