Abstract 3245: Identification of potent, dual PIM/FLT3 kinase inhibitors for AML treatment.

Abstract

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

Design and Preparation of β‐Lactam Derivatives Bearing Phenanthrenimidazole as Cytotoxic Agents

“…Synthesis of new phenanthroimidazole substituted β-lactam derivatives 10 a-p. ChemistrySelect prevent microtubule formation by interaction through the colchicine binding site, while presenting good pharmacokinetic properties and the ability to overcome multidrug resistance in various cell lines. [10] Imidazoles used clinically to treat cancers include azathioprine, [11] dacarbazine, [12] zoledronic acid, [13] tipifarnib, [14] and nilotinib. [15] All inhibit tubulin polymerization through the colchicine-binding site.…”

A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia

“…Since PIM kinases have emerged as important effectors and mediators of FLT3-ITD activity, we hypothesized that dual inhibition of FLT3 and PIM kinases could lead to improved efficacy and be a promising approach in overcoming the rapid development of resistance to such agents [ 25 , 36 – 38 ]. We have recently developed first-in-class, dual PIM/FLT3 kinase inhibitor, the SEL24-B489 compound, and profiled its activity in in vitro and in vivo AML models [ 39 ]. Herein, we show that SEL24-B489 specifically inhibits PIM- and FLT3-ITD- related pathways and exhibits significantly broader anti-tumor activity in AML models than selective FLT3-ITD or PIM inhibitors, underscoring its therapeutic potential for the treatment of AML.…”