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.
- Received December 13, 2017.
- Revision received May 5, 2018.
- Accepted January 14, 2019.
- Copyright ©2019, American Association for Cancer Research.