Dual Inhibition of Aurora and FLT3 Kinases by CCT137690: A Novel Treatment Strategy Against FLT3-ITD Positive AML In Vitro and In Vivo

Abstract 3289

The Aurora kinases are a family of serine-threonine kinases that play key roles in different stages of mitosis. Over-expression of Aurora kinases has been demonstrated in a range of malignancies including leukemia. Aurora kinase inhibitors are emerging as promising agents in the treatment of acute myeloid leukemia (AML) with a number of compounds currently being assessed in clinical trials (Moore AS et al, Leukemia 2010). CCT137690, an imidazo[4,5-b]pyridine derivative discovered at our Institute, is an orally bioavailable, potent, pan-Aurora and FLT3 inhibitor with low nanomolar IC₅₀ values against Aurora A (15 nM), Aurora B (25 nM), Aurora C (19 nM), and FLT3 (<0.5 nM) kinases. CCT137690 showed in vitro and in vivo activity in human colon cancer cell lines and xenograft models (Bavetsias V et al, J Med Chem 2010). Here we report the in vitro and in vivo activity of CCT137690 in FLT3-ITD positive AML. In vitro, the FLT3-ITD positive cell lines MV-4-11 and MOLM-13 are particularly sensitive with GI₅₀ values less than 50 nM. Cellular assays demonstrate that CCT137690 inhibits autophosphorylation of Aurora A, Aurora B and Aurora C kinases and phosphorylation of histone H3, a direct target of Aurora B kinase. CCT137690 also inhibits autophosphorylation of FLT3 and phosphorylation of its downstream targets STAT5 and p44/42 MAPK (Erk1/2). Dual inhibition of Aurora and FLT3 kinases in FLT3-ITD positive AML with CCT137690 induces apoptosis and results in a unique cell cycle profile with cells accumulating in G2/M, whilst selective FLT3 inhibition with MLN518 resulted in G1/S arrest. When given orally to athymic mice, CCT137690 achieved target modulation and potently inhibited the growth of subcutaneous MOLM-13 xenografts, with no obvious toxicity or loss of body weight. Inhibition of MOLM-13 xenograft growth was more pronounced with CCT137690 compared to the selective FLT3 inhibitor MLN518, suggesting that dual inhibition of Aurora and FLT3 kinases may have advantages compared to selective FLT3 inhibition alone. The potent preclinical activity of CCT137690 in FLT3-ITD positive AML models supports the growing body of evidence that dual pan-Aurora and FLT3 kinase inhibitors may be of benefit in the high-risk group of patients with FLT3-ITD positive AML.