Pim-1 and -2 are constitutively active Ser/Thr protein kinases involved in cytokine signal transduction and the regulation of cell survival.  Pim kinases have been found to be over-expressed in solid tumors, in multiple myeloma and in a variety of hematopoietic malignancies such as leukemia.  High-throughput screening of Amgen's compound collection followed by an initial round of compound optimization led to 1,3,4-thiadiazole-based Pim-1/2 inhibitor 1 .  Replacement of the aminothiadiazole motif with an aminooxadiazole led to improvements in the series pharmacokinetics (PK).  X-ray crystallographic studies guided the replacement of the 6-isopropoxypyridinyl group with a cyclopropylpyrimidine and resulted in compound 2  with enhanced potency in Pim-1 and -2 enzymatic and cell assays.

Discovery and optimization of aminooxadiazoles as potent proviral integration site of Moloney murine leukemia virus kinases (Pim) inhibitors

248th National Meeting (2014)

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