The Pim serine-threonine kinase family is composed of three members that play an important role in intracellular signaling and contribute to pathways involved in cell survival, proliferation, stress response and cellular motility. Out the three family members, Pim-1 has been studied most extensively and was shown to be a crucial downstream effector of several oncogenes such as Jak2 and FLT3 kinases. Pim-1 overexpression has been also reported in a variety of cancers such as diffuse B cell lymphoma, chronic lymphocytic leukemia, Flt3-mediated acute myelogenous leukemia and solid tumors including prostate and pancreatic cancers. For this reason, Pim-1 kinase emerged as a novel and interesting target of significant potential for therapeutic intervention.
In the current study, the optimization of the initial lead compound - which presented moderate potency in Pim kinase inhibition, low solubility and bioavailability - led to identification of a novel group of orally bioavailable Pim kinase inhibitors. Among the newly synthesized compounds several derivatives exerted increased potency in Pim kinase inhibition with IC50 values below 5 nM. Profiling of best inhibitors on a KINOMEscanTM Max kinase panel revealed superior selectivity towards Pim kinases. Anticancer activity of these new derivatives was investigated in various neoplastic cell lines of hematological and solid tumor origin where the compounds were shown to induce apoptosis both as a single agent, but also synergistically with standard therapies, such as docetaxel, sunitinib and rapamycin. FACS analyses revealed accumulation of subG0 phase, indicating apoptosis in time and concentration dependant manner. In the living cells, two phenotypes could be observed, namely a cell cycle arrest of the cells either in the G0/G1 or G2/M phases, depending on the cell line.
In order to confirm that the observed cytotoxic and cell cycle effects were due to inhibition of the Pim kinases, we performed analyses of direct downstream substrates of these kinases. Pim kinases were shown to phosphorylate p27KIP1, 4E-BP1 and Bad proteins, and treatment of cells in vitro with our new compounds caused a dramatic reduction in the phosphorylation levels of these targets. Best performing compounds were chosen for an efficacy screen in a mouse xenograft model, proving their anticancer activity. Results of Selvita’s Pim kinase inhibitor optimization efforts are shown and discussed, supporting further development of this class of inhibitors in oncology indications.

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