A kinase inhibitor with anti-Pim kinase activity is a potent and selective cytotoxic agent towards acute myeloid leukemia

Abstract

More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3-a]carbazole-3-carbaldehyde, pyrazolo[3,4-c]carbazole, pyrazolo[4,3-a]phenanthridine or pyrrolo[2,3-g] indazole. The compounds were inhibitors of Pim-kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim-kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC50 below 5 μM, and was ten times less potent against non-malignant cells. It perturbed Pim kinase mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in AML patient blasts, including blast carrying high-risk FLT3-ITD mutation. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity towards patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in pre-clinical animal models for AML.