Abstract 2826: Preclinical development of a Pim kinase inhibitor for cancer treatment

Abstract

Abstract Pim kinases were identified as the crucial downstream effectors various important oncogenes like Jak, FLT3 or Ras kinases. Multiple targets phosphorylated by Pim kinases, such as 4EBP1, p21Waf, p27KIP1, c-Myc or CXCR4 play important roles in intracellular signaling and contribute to pathways involved in cell survival, proliferation, stress response and cellular motility. Moreover, the significance and relevance of Pim kinases as valid therapeutic targets is further confirmed by their expression levels in variety of cancer types, especially in various types of lymphomas, leukemias or myelomas. For example Pim kinase overexpression contributes to the development of diffuse large B cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic leukemia and FLT3-mediated acute myelogenous leukemia. As members of the family, Pim-1, Pim-2 and Pim-3 were shown to be prevent apoptosis, promote protein translation and cell survival thereby enhancing proliferation of malignant cells, Pim kinases emerged as a novel and interesting target with significant potential for therapeutic intervention in cancer. In the current study we are reporting the results of a second generation small molecule Pim kinase inhibitors that were developed by Selvita and results for the best characterized potent Pim kinase inhibitor developed so far. The small molecule inhibitors exert high potency in vitro both on all three Pim kinases as well as on a large panel of cancer cell lines. Mechanism of action for selected compounds was confirmed both in vitro in variety of cell lines and in vivo in xenograft models by downregulation of c-Myc and 4EBP1 phosphorylation inhibition. Selected compounds were tested in a range of combinations with standard anti-cancer therapeutics in both leukemias and solid tumor cell lines and showed potent synergistic effects. Strong synergies were observed particularly in combination with targeted therapies like the PI3K/Akt pathway inhibitors or Jak kinase inhibitors. Data will be presented on in vivo efficacy of lead compounds examined in xenograft models. Additionally, the results of safety assessment of the lead compound will be presented revealing preferable safety profile with no effect on ion channel mediated cardiotoxicity and favorable pharmacokinetic profile. Taken together, presented data will further support the rationale of using Pim kinase inhibition as a novel approach to standalone cancer therapy, and in combination with other targeted and cytotoxic therapies, especially to overcome developing drug resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2826. doi:1538-7445.AM2012-2826