Abstract 4428: A novel imidazo[4,5-b]pyridine Aurora kinase inhibitor with anti-leukemic activity

Abstract

Abstract The Aurora kinases are a family of highly conserved serine-threonine kinases that play key roles in several stages of mitosis. Over-expression of these 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) and chronic myeloid leukemia (CML). The activity of this class of drugs in AML and CML may be in part due to their ability to also inhibit the tyrosine kinases FLT3 and Abl1 respectively. Here we report the activity of a novel imidazo[4,5-b]pyridine derivative developed at our institution with potent inhibition of Aurora A and B kinases (IC50 values of 6 nM and 45 nM respectively). Furthermore, the IC50 for FLT3 kinase is < 0.5 nM, whilst the IC50 for Abl1 kinase is 82 nM. Consistent with the potent kinase inhibition profile, the AML cell lines MV-4-11 and MOLM-13 are particularly sensitive with GI50 values less than 50 nM. Cellular assays demonstrate that this imidazo[4,5-b]pyridine derivative inhibits phosphorylation of histone H3, a direct target of Aurora B kinase, as well as phosphorylation of FLT3 and the downstream p44/42 MAP kinases in these cell lines. Both MV-4-11 and MOLM-13 carry internal tandem duplications of the FLT3 receptor tyrosine kinase (FLT3-ITD), which is clinically associated with a poor prognosis in AML. The potent preclinical activity in FLT3-ITD positive cell lines 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. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4428.