Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 tyrosine kinase inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples restores cell sensitivity to FLT3 inhibitors. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. For such reasons, we have developed SEL24-B489 - a potent, dual PIM and FLT3-ITD inhibitor. SEL24-B489 exhibited significantly broader on-target activity in AML cell lines and primary AML blasts than selective FLT3-ITD or PIM inhibitors. SEL24-B489 also demonstrated marked activity in cells bearing FLT3 tyrosine kinase domain (TKD) mutations that lead to FLT3 inhibitor resistance. Moreover, SEL24-B489 inhibited the growth of a broad panel of AML cell lines in xenograft models with a clear pharmacodynamic-pharmacokinetic relationship. Taken together, our data highlight the unique dual activity of the SEL24-B489 that abrogates the activity of signaling circuits involved in proliferation, inhibition of apoptosis and protein translation/metabolism. These results underscore the therapeutic potential of the dual PIM/FLT3-ITD inhibitor for the treatment of AML.
Starting from (+)-3-carene 1, naturally occurring bicyclic, monoterpene hydrocarbon, (-)-ciscarane-4-one 3 was obtained as a result of the two-step synthesis. Our investigations were focused on the optimization of chemical Baeyer-Villiger reaction of 3 leading to ε-lactones. A mixture of terpenoid lactones 4a, 4b was obtained and next separated using column chromatography. The pure compounds were subjected to the evaluation of antifeedant activity towards three species of storage insects. Fusarium culmorum, Fusarium oxysporum and Aspergillus niger were chosen among six fungal strains to perform microbiological BaeyerVilliger oxidation. As a result, three derivatives were isolated and characterized by spectroscopic methods.
Acute myeloid leukemia (AML) is a highly heterogeneous disease with numerous signaling pathways that contribute to its pathogenesis. Advances in our understanding of molecular mechanisms of AML pathogenesis and prognosis so far did not translate into significant clinical improvements. AML is still the highest unmet medical need within hematological malignancies area, particularly in case of the elderly patients. FLT3 inhibitors were investigated in the recent years as possible therapeutic agents, however to date the clinical trials of FLT3 inhibitors have yielded disappointing results. On the other hand, PIM kinases have been identified in the last years as critical downstream components of FLT3 signaling, especially in the case of oncogenic FLT3 mutants. PIM kinases are being overexpressed in a range of hematopoietic malignancies and solid cancers and the overexpression of PIMs is associated with a poor prognosis and decreased survival of patients suffering from cancer. In many cases also, PIM overexpression was associated with development of drug resistance. As dual and simultaneous inhibition of various pathway components is an emerging therapeutic idea, exemplified by several compounds in development for cancer treatment, we have developed a series of dual PIM/FLT3 small molecule inhibitors to investigate this concept. Similarly to examples of small molecule inhibitors from the JAK/STAT or PI3K/AKT pathways, where compounds are being developed as a way to improve efficacy, resistance development and overcoming the negative feedback loops, often seen after single target inhibition, we have observed increased potency of compounds developed in this series of dual PIM/FLT3 inhibitors. Synthesized inhibitors showed higher activity towards mutated FLT3 (FLT3-ITD and other FLT3 mutants) than wild type kinase and the selectivity profile on a panel of 450 kinases was comparable to best clinical examples of kinase inhibitors. In contrast to selective PIM inhibitors, the treatment with dual PIM/FLT3 inhibitors showed potent apoptosis induction as a results of Erk and S6 phosphorylation inhibition. The in vitro activity in FTL3-ITD positive cells was also confirmed in vivo in a PK/PD xenograft experiment, where sustained biomarker inhibition was observed already after single compounds administration. Oral administration of dual PIM/FLT3 inhibitors led to potent effect in vivo and in certain cases also to remissions in subcutaneous xenograft models. Observed activity profile and synergistic effects observed with other targeted therapies and standard of care compounds, makes dual PIM/FLT3 inhibitors an exciting approach for treatment of FLT3-mutant positive AML patients with high chances of clinical success. Citation Format: Wojciech Czardybon, Michal Galezowski, Renata Windak, Magdalena Salwińska, Izabela Dolata, Ewa Trebacz, Radosław Obuchowicz, Pawel Guzik, Magdalena Zawadzka, Ewelina Wincza, Katarzyna Wiklik, Mariusz Milik, Malgorzata Zurawska, Karolina Krawczynska, Krzysztof Brzózka. Identification of potent, dual PIM/FLT3 kinase inhibitors for AML treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3245. doi:10.1158/1538-7445.AM2013-3245
Herewith, we report development of small molecule inhibitors of MNK1 and MNK2 kinases and their cellular activity. MNK1 and 2 are MAP kinase-interacting kinases are activated by RAS and MAPK signaling pathways, and are involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4e on a conserved serine 209. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in diverse types of cancer. Interestingly, mice that lack both Mnk1 and Mnk2 do not have any apparent phenotype. Recently first dual MNK1/MNK2 inhibitors have entered clinical trials as a combinational therapy with docetaxel in NSCLC. SEL201 is a series of small molecule inhibitors which inhibit activity of both MNK1 and MNK2 in a low nM range and high selectivity confirmed in kinome panels. Analysis of SEL201 cellular activity indicated potent inhibition of eIF4e Ser209 in vitro in cancer cells and in vivo after oral administration in xenograft tumors. Repressed phosphorylation of eIF4e resulted in impaired translation of several proteins involved in metastasis and activation of immune cells. High potency, selectivity and favorable ADME/PK profile indicates that SEL201 inhibitors would be useful tools in probing molecular consequences of eIF4e Ser209 inhibition in cancer cells. SEL201 in vitro and in vivo activities on viability and metastasis will be presented in cellular and in vivo models of solid tumors and hematological malignancies. SEL201 series is further developed as a cancer therapy with a good therapeutic window. Citation Format: Tomasz Rzymski, Agnieszka Dreas, Ewelina Wincza, Charles-Henry Fabritius, Urszula Kulesza, Katarzyna Kucwaj- Brysz, Mariusz Milik, Aniela Gołas, Renata Windak, Eliza Żyłkiewicz, Anna Wróbel, Maciej Sułkowski, Krzysztof Brzózka. Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C194.
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