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Aurora kinases have been implicated in the onset of several human cancers. They are overexpressed in different tumor types including colon, breast, pancreatic cancers as well as in leukemias. AS703569 (formerly known as R763) is an orally bioavailable inhibitor of all three aurora kinase isoforms: A, B and C and is currently in Phase I clinical studies for solid tumors. AS703569 also exhibits potent inhibition of the receptor tyrosine kinase, FLT3. FLT3 is postulated to play an important role in the pathogenesis of AML. Somatic mutations of FLT3 resulting in constitutive kinase activation are the most common acquired genomic abnormality found in this disease. We are therefore exploring the potential therapeutic benefits of AS703569 as a dual aurora kinase/FLT3 inhibitor in AML.

We tested the anti-proliferative effect of AS703569 in a panel of AML cell lines harboring different genetic defects. All cell lines were potently inhibited by AS703569 with IC50s between 0.4 and 40 nM. The MV4-11 cell line possessing a FLT3 ITD mutation was 10-fold more sensitive to AS703569 inhibition than other cell lines. The compound also showed a dose-dependent inhibition of FLT3 phosphorylation in these cells, albeit with a decrease in potency suggesting that FLT3 regulation does not account for the full anti-proliferative effect of AS703569.

We also tested the anti-tumor activity of AS703569 in two leukemia xenograft mouse models: MV4-11 and HL-60. In the MV4-11 model, tumors were grown to different sizes: 230, 750, and 1100 mm3,and in all three experimental conditions, tumors were completely regressed after one dose (75 mg/kg) of AS703569. We found that a weekly dosing schedule is best tolerated by mice and reproducibly shows potent anti-tumor activity. Consistent with our in vitro data, AS703569 was less potent in the HL-60 xenograft model where the FLT3 mutation is absent. In this model, AS703569 only partially inhibited tumor growth.

Taken together, our data suggest that AS703569 shows particularly promising therapeutic activity in FLT3-driven AML.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA