The Aurora family of serine/threonine kinases, which consists of Aurora A, B and C, plays an important role in chromosome alignment, segregation, and cytokinesis during mitosis. Tozasertib is a potent inhibitor of all three Aurora kinases, with Ki(app) values of 0.6 nM, 18 nM and 4.6 nM for Aurora A, B and C, respectively, and showed much less potency to FLT3 and Bcr-Abl with Ki(app) values of 30 nM. Tozasertib potently inhibited the proliferation of a wide variety of tumor cell types from different original tissues with IC50 values ranging in 15-113 nM, including HCT116, LS174T (colorectal), HL60 (leukemia), MD-MBA-231, ZR-75-1, MCF-7 (breast), PC3 (prostate), MIA PaCa2 (pancreatic), A375 (melanoma) and HeLa (cervical). In a further study, it was found that leukemia, lymphoma and colorectal cancer cell lines were particularly sensitive to Tozasertib on growth inhibition attributable to apoptosis. Tozasertib can cause accumulation of HeLa cells with ≥4N DNA content and inhibits histone H3 phosphorylation on Ser10, suggesting the inhibition of Aurora B. These can also be observed in in vivo model. Tozasertib at 75 mg/kg, twice a day intraperitoneally, caused mean tumor volumes reduced by 98% in a human AML (HL-60) xenograft model. Administration of Tozasertib by i.v. infusion at 1 mg/kg/h, 3 d per week, caused tumor regression in four of seven nude rats bearing established HCT116 (colon) tumors[1].
作用机制
Tozasertib binds to the ATP-binding site of the Aurora kinases.[1]
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