Overexpression of Proviral Insertion of Moloney virus (PIM) 1, 2 and 3 kinases is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias. Pan-PIM 1, 2 and 3 kinase inhibitors have recently begun to be tested in humans to assess whether pan PIM kinase inhibition may provide benefit to cancer patients. We discovered a potent and selective pan-PIM kinase inhibitor, PIM447, which is currently being assessed in phase IB studies of patients with hematological malignancies. A key structural motif of PIM447 is the 1,3-cis-disubstituted cylcohexyl amine, where the amino group participates in H-bond interactions with the PIM protein residues which are crucial for potency. In the early stage of the discovery of PIM447, we were interested in replacing the amino group with isosteres such as a hydroxyl group as an alternative H-bond acceptor and donor. In this presentation, the cellular potency and metabolic stability of cyclohexyl diol inhibitors of pan-PIM kinases will be reported.  In addition, the synthesis of synthetically challenging tetra-substituted cyclohexyl diol intermediates will be described.

Synthesis and Structure–Activity Relationship (SAR) of tetra-substituted cyclohexyl diol inhibitors of pan-PIM kinases

254th National Meeting (2017)

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