Abstract 1749: Preclinical characterization of SEL24-B489, a dual PIM/FLT3 inhibitor for the treatment of hematological malignancies

Abstract

Abstract PIM kinases represent an emerging therapeutic target in multiple hematological malignancies, as exemplified by currently ongoing phase I clinical trials by Astra Zeneca (AZD1208) and Novartis (LGH447) in acute myeloid leukemia and multiple myeloma. Selvita has developed a potent and selective dual PIM/FLT3 mutant kinase inhibitor - SEL24-B489 showing high inhibitory activity on all three PIM kinase isoforms and FLT3 kinase mutants. We have previously reported that PIM kinases are important downstream effectors of FLT3 signaling and play a crucial role in cell survival and inhibition of apoptosis upon expression. Due to heterogeneous nature of AML, dual inhibition of FLT3 mutant kinase and PIM kinases led to improved efficacy of our compound in comparison to selective inhibitors of either PIM of FLT3 kinases. Herewith, we would like to report further progress of characterizing the B489 inhibitor beyond AML. We assessed PIM kinase expression levels in a panel of lymphoid malignancies and found that PIM1 and PIM2 exhibit high expression levels in a fraction of mantle cell lymphoma (MCL), diffuse large-B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin's lymphoma (HL), chronic lymphocytic leukemia (CLL) and mucosa associated lymphoid tissue-type (MALT) lymphoma cell lines and primary tumors . High levels of PIM kinases were associated with certain established adverse prognostic factors and clinical outcome of the patients and correlated with aggressiveness of the disease in some of these tumors. Inhibition of PIM kinases with tool inhibitors was shown to influence cellular proliferation and, translational inhibition of 4EBP1 as reported in the literature. In addition, SEL24-B489 inhibited NFκB activity and decreased CXCR4 expression. Comparison of SEL24-B489 to competitive PIM inhibitors revealed higher cellular activity and biomarker response, as shown by inhibition of phospho-S6 phosphorylation in sub-microM concentrations. The presented data will further validate SEL24-B489 as a successful example of rational drug design and present a promising therapeutic approach in multiple hematological malignancies, both stand alone and in combination with standard of care and targeted therapies in clinical development. Citation Format: Wojciech Czardybon, Renata Windak, Izabela Dolata, Magdalena Salwińska, Maciej Szydlowski, Tomasz Sewastianik, Emilia Białopiotrowicz, Elżbieta Mądro, Ewa Lech-Marańda, Bożena K. Budziszewska, Katarzyna Borg, Przemysław Juszczynski, Krzysztof D. Brzózka. Preclinical characterization of SEL24-B489, a dual PIM/FLT3 inhibitor for the treatment of hematological malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1749. doi:10.1158/1538-7445.AM2014-1749