COTI-2

COTI-2 (COTI2) is an orally available thiosemicarbazone that may act on mutant forms of p53 and PI3K/AKT/mTOR pathway; induces apoptosis in a wide variety of human tumor cells in culture (IC50s<40 nM), inhibits the proliferation of colorectal cancer cell lines more effectively than cetuximab and erlotinib; shows superior activity against tumor, and is safe and well-tolerated in vivo.Ovarian Cancer Phase 1 Clinical (In Vitro) :COTI-2 efficiently inhibits the proliferation rate of all the tested cell lines following 72 h of treatment. COTI-2 is significantly effective at inhibiting tumor cell proliferation in all three cell lines (COLO-205, HCT-15, and SW620) . Relatively low concentrations of COTI-2 are active against all human glioblastoma cell lines tested (U87-MG, SNB-19, SF-268, and SF-295) . COTI-2 treatment of SHP-77 cells with approximate IC50 concentrations results in the induction of early apoptosis among 40 to 47% of total cells. (In Vivo) :COTI-2 significantly inhibits tumor growth in the HT-29 human colorectal tumor xenografts at a dose of 10 mg/kg. In addition to reducing tumor volumes at specific times post-treatment, COTI-2 also delays the time required for tumors to reach specified volumes. COTI-2 also significantly inhibits tumor growth in the SHP-77 SCLC xenograft model at a dose as low as 3 mg/kg. COTI-2 treatment both reduces U87-MG tumor volumes at specific times post-treatment and lengthens the time required for U87-MG xenografts to grow in nude mice. Control tumors in mice treated with vehicle alone take only 5 days to reach an average volume of 828 mm3 while tumors in animals treated with COTI-2 take double that time (10 days) to reach a similar mean volume (857 mm3) . COTI-2 treatment effectively inhibits OVCAR-3 xenograft growth regardless of the route of administration.