Background:

SCH-1473759 is an aurora inhibitor with IC50s of 4 and 13 nM for aurora A and B, respectively.

SCH-1473759 directly binds to aurora A and B with Kds of 20 and 30 nM, respectively. SCH-1473759 also inhibits the Src family of kinases (IC501000 nM) against 34 other kinases representing different families of the kinome. SCH-1473759 inhibits HCT116 cells proliferation with an IC50 of 6 nM[1]. SCH 1473759 inhibits tumor cell lines from different tissues (breast, ovarian, prostate, lung, colon, brain, gastric, renal, skin, and leukemia). The most sensitive cell lines includ A2780, LNCap, N87, Molt4, K562, and CCRF-CEM with IC50 values<5 nM[2].

SCH-1473759 at a low dose of 5 mg/kg (ip, bid) is well-tolerated in a continuous dosing schedule and shows 50% tumor growth inhibition(TGI) on day 16. A higher dose of 10mg/kg(ip, bid) is well-tolerated in an intermittent schedule (5 days on, 5 days off) and gave 69% TGI on day 16. SCH-1473759 shows good exposure in all species with the clearance being high in rodents and moderate in dog and monkey. The half-life is also moderate, but the tissue distribution is high[1]. SCH 1473759 dose- and schedule-dependent anti-tumor activity in four human tumor xenograft models. Further, the efficacy is enhanced in combination with taxanes and found to be most efficacious when SCH 1473759 is dosed 12-h post-taxane treatment[2].

参考文献:
[1]. Yu T, et al. Discovery of a Potent, Injectable Inhibitor of Aurora Kinases Based on the Imidazo-[1,2-a]-Pyrazine Core. ACS Med Chem Lett. 2010 Jun 7;1(5):214-8.
[2]. Basso AD, et al. SCH 1473759, a novel Aurora inhibitor, demonstrates enhanced anti-tumor activity in combination with taxanes and KSP inhibitors. Cancer Chemother Pharmacol. 2011 Oct;68(4):923-33.