Abstract A243: Novel Pim kinase inhibitors for treatment of hematological malignancies and solid tumors.

Abstract

Abstract The family of Pim kinases emerged as a novel and interesting target with significant potential for therapeutic intervention in cancer. All three 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 seem to be crucial downstream effectors various important oncogenes like Jak, Flt3 or Ras kinases. Multiple targets phosphorylated by Pim kinases 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 of both hematological origin. For example Pim kinase overexpression contributes to the development of diffuse B cell lymphoma, mantle cell lymphoma, B-cell chronic lymphocytic leukemia and Flt3-mediated acute myelogenous leukemia. Interestingly, accumulating literature data point towards emerging role of Pim kinases also in development of malignancies that originate from epithelial cells, especially gastric, colon and hepatocellular cancers, but also prostate and pancreatic cancers. In this study we are reporting the results for novel small molecule Pim kinase inhibitors that were developed by Selvita. in Currently, we are performing a lead optimization program of novel, small molecule pan-Pim kinase inhibitors. Compounds developed within the SEL24 series exert high potency in vitro both on all three Pim kinases as well as on a large panel of cancer cell lines. Among synthesized compounds we have identified most selective Pim kinase inhibitors described so far with selectivity scores on a panel of 290 kinases inhibited over 90% at 1 μM concentration was equal to 1.8%. 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. Further experiments indicated that our compounds induced both apoptotic cell death and cell cycle arrest at G0/G1, consistently with the predicted Pim kinase inhibition phenotype. SEL24 compounds showed mostly synergistic effects in a range of combinations with standard anti-cancer therapeutics in both leukemias and solid tumor cell lines. Strong synergies were observed not only for cytotoxic agents like docetaxel, gemcitabine or cyratabine, but also for targeted therapies like the PI3K/Akt pathway inhibitors or Jak kinase inhibitors. Data will be presented on in vivo efficacy of SEL24 lead compounds examined in xenograft models of leukemias, lymphomas and solid tumors (lung and colon cancer). Apart from excellent efficacy in in vivo xenograft models, SEL24 compounds show preferable safety profile with no effect on ion channel mediated cardiotoxicity and favorable pharmacokinetic profile. Taken together, presented data supports 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 AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A243.