A Kinase Inhibitor with Anti-Pim Kinase Activity is a Potent and Selective Cytotoxic Agent Toward 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 EC 50 below 5 mmol/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.

NF-κB: A Druggable Target in Acute Myeloid Leukemia

“…PIM kinases promote NF-κB constitutive activation and at the same time it is regulated by NF-κB. Several PIM kinase inhibitors, such as AZD1208, SMI-4a, SGI-1776, YPC-21440 and YPC-21817, have been shown to inhibit the growth of AML cells in vitro and in vivo [ 86 , 88 , 175 , 176 ]. The most advanced PIM1 inhibitor, SEL24/MEN1703, which inhibits both PIM1 and FLT3, is currently in clinical trial for AML patients.…”

Synthesis of new pyrazolo[4,3-a]phenanthridine Pim-1 inhibitors and evaluation of their cytotoxic activity towards the MOLM-13 acute myeloid leukemia cell line

“…Compounds 20 and 21 substituted at the 1-position showed improved Pim-1 inhibitory potency and induced apoptosis in AML MOLM-13 cells, however without reaching a cytotoxicity as potent as that of VS-II-173. This could be due to the efficient targeting by VS-II-173 of other cellular targets (VS-II-173 is a multi-kinase inhibitor 5 ) and/or to a different 10 cellular distribution of 20/21 within the cellular compartments due to their higher lipophilicity (20 and 21 cLopP = 1.99 and 2.21, 15 respectively, instead of 1.46 for VS-II-173). In addition, compound 20 and 21 showed low cytoxicity toward non-cancerous NRK cells.…”

“…4 Derivatives substituted at the 5-, 8-, 9-and 10-positions were synthesized 4 and compound VS-II-173 was identified as a potent and selective cytotoxic agent toward AML patient blasts including some carrying mutations associated with poor diagnosis (Figure 1). 5 Importantly, it was demonstrated that substitution at the 5-position by a nitro group was crucial for potent Pim inhibition. Moreover, molecular modelling studies showed that the nitro group of VS-II-173 could be involved in hydrogen bonding with the ATP binding site of Pim.…”

Biological Therapies in the Treatment of Cancer—Update and New Directions

“…Currently, inhibitors are tested for many protein kinases, including PIM serine-threonine kinases 1, 2 and 3. PIM kinases are overexpressed in AML and solid tumors such as colon cancer or prostate tumor, which is associated with poor prognosis [221][222][223]. Pan-Pim kinase inhibitors from the imidazopyridazine-thiazolidinediones group have been shown to exert anti-neoplastic activity in various neoplastic types in vitro and in vivo [224].…”