Proviral Insertion of Moloney virus (PIM) 1, 2 and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells.  Over expression of PIM1, 2 and 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias.  PIM1 was discovered as an oncogene in mice, where PIM1 over expression driven by proximal insertion of the Moloney provirus results in lymphoma.  As such, there is interest in determining whether selective Pim inhibition can improve outcomes of human cancers with over expressed PIMs.  Herein, we describe our initial efforts towards this goal.  The structure guided optimization of a singleton HTS hit in which the potency against all three Pim isoforms was increased >10,000 fold to yield compounds with pan Pim Ki's <10 picoM is described.  Within this series a compound was identified with suitable PK properties and kinase selectivity to establish a PK/PD-efficacy relationship in both acute myeloid leukemia (KG-1 cell line, Pim1 over expression) and multiple myeloma (KMS11-luc cell line, Pim2 over expression) as determined by in vivo inhibition of pS6RP phosphorylation and tumor growth inhibition in mouse xenograft models.

Structure guided optimization of novel, selective, and orally bioavailable inhibitors of Pim kinases

245th National Meeting (2013)

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