AZD1208, a Novel, Potent and Selective Pan PIM Kinase Inhibitor, Demonstrates Efficacy in Models of Acute Myeloid Leukemia

Abstract 1540

The PIM serine/threonine kinase family is composed of three highly homologous members; PIM1, PIM2 and PIM3, identified by the ability of the prototype member PIM1 to drive lymphomagenesis in mice. Upregulation of PIM1 and PIM2 is observed in leukemias and lymphomas, including AML, NHL and CLL, highlighting the potential of these kinases as therapeutic targets in these indications. PIMs are downstream effectors of many cytokine and growth factor signaling pathways and are direct transcriptional targets of STAT transcription factors activated by these pathways. PIMs can phosphorylate multiple substrates to mediate cell proliferation and survival. Here we describe the function of AZD1208, an orally available, potent and highly selective PIM inhibitor that effectively inhibits all three isoforms. AZD1208 inhibits the growth of several AML cell lines and sensitivity correlates with the level of PIM1 expression, STAT5 activation and presence of protein tyrosine kinase mutation. AZD1208 causes cell cycle arrest and apoptosis in MOLM-16 cells in culture. This is accompanied by a dose-dependent reduction in pBAD serine 112 and other substrates, as well as an increase in cleaved caspase 3. AZD1208 suppresses the growth of MOLM-16 and KG-1a xenograft tumors in vivo in a dose proportional manner. In addition, AZD1208 leads to potent inhibition of colony growth of primary AML cells from bone marrow aspirates and downregulates phosphorylation of PIM targets. These results underscore the therapeutic potential of PIM kinase inhibition by AZD1208 for the treatment of AML.