Discovery of PIM Kinase Inhibitor: 1,3,4-oxadiazole-2(3H)-thione Analogs
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PIM kinases that consist of three isoforms, PIM-1, PIM-2, and PIM-3 play a critical role in regulating cell cycle, survival, proliferation, and the homing and migration. PIM kinases have been found to be upregulated in various human hematological and solid tumors. Therefore, the PIM kinases represent potential drug targets for anticancer therapy. To achieve highly potent and selective PIM kinase inhibitors, unique structural features in the ATP-binding pocket of PIM kinases were targeted. We performed a structure-based drug design using the AutoDock vina program and the X-ray crystal structures of human PIM kinases and identified a series of 1,3,4-oxadiazole-2(3H)-thione analogs as promising PIM kinase inhibitors.
Abstract
PIM kinases that consist of three isoforms, PIM-1, PIM-2, and PIM-3 play a critical role in regulating cell cycle, survival, proliferation, and the homing and migration. PIM kinases have been found to be upregulated in various human hematological and solid tumors. Therefore, the PIM kinases represent potential drug targets for anticancer therapy. To achieve highly potent and selective PIM kinase inhibitors, unique structural features in the ATP-binding pocket of PIM kinases were targeted. We performed a structure-based drug design using the AutoDock vina program and the X-ray crystal structures of human PIM kinases and identified a series of 1,3,4-oxadiazole-2(3H)-thione analogs as promising PIM kinase inhibitors.
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