Identification of N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies

Recent studies have begun testing pan PIM kinase inhibitors, targeting PIM1, PIM2, and PIM3, in humans to evaluate their potential benefits for cancer patients. This paper describes the synthesis, in vitro activity, in vivo efficacy in an acute myeloid leukemia xenograft model, and preclinical profile of the potent and selective pan PIM kinase inhibitor, compound 8 (PIM447). Building on the previously reported aminopiperidyl pan PIM kinase inhibitor, compound 3, a strategy was developed to enhance microsomal stability, leading to the discovery of potent aminocyclohexyl pan PIM inhibitors with improved metabolic stability. Compound 8, derived from this aminocyclohexyl series, entered clinical trials in 2012 for multiple myeloma patients and is currently undergoing several Phase 1 trials in LGH447 cancer patients with hematological malignancies.