N-(4-(4-((5-(2-Methoxyethoxy)pyrazin-2-yl)thio)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide 4-methylbenzenesulfonate

T-1101 tosylate (TAI-95 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[1]

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Hec1/Nek2[1]

T-1101 tosylate shows potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM)[1]. T-1101 tosylate disrupts the Hec1/Nek2 protein–protein interaction in the cells[1]. T-1101 tosylate (1μM; 3-24 24 hours) decreases the level of Nek2 in a time-dependent manner[1]. T-1101 tosylate (1 µM; 24 hours) induces apoptosis[1]. T-1101 tosylate reduces amounts of cell-cycle related proteins cyclin A1, cyclin B1, and cyclin D1[1]. Apoptosis Analysis[1] Cell Line: HeLa cells Concentration: 1 µM Incubation Time: 24 hours Result: Increased the amount of apoptotic marker proteins cleaved caspase-3 and PARP and decreased the amount of antiapoptotic proteins Mcl-1 and XIAP in HeLa cells. Western Blot Analysis[1] Cell Line: K562 cells Concentration: 1 μM Incubation Time: 3 hours, 6 hours, 16 hours, 24 hours Result: Lowered the level of Nek2 in a time-dependent manner.

T-1101 tosylate shows good oral bioavailability and thermal stability [1]. Oral co-administration of T-1101 tosylate (2.5 mg/kg; p.o.; twice per day) halves the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts [1]. T-1101 tosylate (2.5 mg/kg; p.o.; twice per day) shows significant in vivo activity in mice bearing various human cancer xenografts[1]. Animal Model: SCID mice bearing human Huh-7, BT-474, MCF-7, and MDA-MB-231 xenografts[1] Dosage: 25 mg/kg, 50 mg/kg Administration: Oral administration; twice per day; 28 days Result: Showed significant in vivo activity in mice bearing various human cancer xenografts.

[1]. Chuang SH, et al. Discovery of T-1101 tosylate as a first-in-class clinical candidate for Hec1/Nek2 inhibition in cancer therapy. Eur J Med Chem. 2020 Apr 1;191:112118.