Aurora kinases, cell cycle-regulated serine/threonine kinases, play a role in regulating mitosis. In detail, the subtype Aurora A usually regulates centrosome maturation and microtubule nucleation. Aurora B regulates chromatin structure in part by phosphorylating proteins such as Histone H3. Additionally, Aurora B monitors biorientation and tension. Moreover, Aurora B regulates cytokinesis via phosphorylation of intermediate filaments and RhoA/Rac-GAP. Not only that, Aurora C functions similarly to Aurora B but expresses in testis and plays a role during spermatogenesis. A large number of studies suggest that disrupting normal Aurora function has the potential for some cancers study.

In this blog, I’d like to introduce another aurora inhibitor SCH-1473759, which exhibits IC<sub>50</sub> values of 4 and 13 nM for Aurora A and B, respectively.

In vitro SCH-1473759 directly binds to aurora A and B with K<sub>d</sub>s of 20 and 30 nM, respectively. SCH-1473759 also inhibits the Src family of kinases (IC<sub>50</sub><10 nM), Chk1 (IC<sub>50</sub>=13 nM), VEGFR2 (IC<sub>50</sub>=1 nM), and IRAK4 (IC<sub>50</sub>=37 nM). Moreover, SCH-1473759 inhibits HCT116 cells proliferation with an IC<sub>50</sub> of 6 nM. SCH 1473759 inhibits tumor cell lines from different tissues (breast, ovarian, prostate, lung, colon, brain, gastric, renal, skin, and leukemia).

In vivo, 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. 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 tissue distribution is high. 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.

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.

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.