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 μmol/L, and was 10 times less potent against nonmalignant 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 patients with AML blasts, including blast carrying high-risk FLT3-ITD mutations. 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 toward 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 preclinical animal models for AML.
Highlights
Acute myeloid leukemia (AML) is a highly heterogeneous disease characterized by aberrant myeloid differentiation and subsequent accumulation of immature myeloid cells in the bone marrow (BM)
Characterization of anti-AML activity of kinase inhibitors We previously found that pyrrolo[2,3-a]carbazole-3-carbaldehyde Pim kinase inhibitors [15] had promising activity against AML cells
The cardiomyoblasts, epithelial cell lines, and the chronic myeloid leukemia cell line K562 were unaffected at VS-II-173 concentrations inducing 100% death in the AML cells
Summary
Acute myeloid leukemia (AML) is a highly heterogeneous disease characterized by aberrant myeloid differentiation and subsequent accumulation of immature myeloid cells in the bone marrow (BM). Pim kinases lack regulatory domains, and are constitutively active [6] Their activity is regulated by altering the intracellular levels, that is by transcription and translation, or by degradation [7]. Together this makes them a likely Achilles heel for AML cells dependent on a reliable communication of cytokine signals to the nucleus in order to survive and multiply. Several Pim kinase inhibitors have been evaluated for therapeutic potential against hematologic disorders, in particular multiple myeloma and AML, and CML, ALL, and B-cell lymphoma [9, 10]. The ATP-binding pocket, along with the substrate-recognition residues are identified as crucial for Pim kinase inhibitors [19]
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