Tools for fragment based drug discovery

Pim-1

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PIM-1


The Pim kinases, Pim-1, -2, pim1_all_xray3and -3, are a class of constitutively active serine/threonine kinases that are highly homologous (60-70%) and are involved in several normal biological process including: cell survival, proliferation, differentiation, and apoptosis. However, when these processes become disrupted or hyperactivated, they can become oncogenic. Mechanistic studies have shown that high expression levels of the Pim kinases are associated with hematologic and epithelial cancers in humans; thus, they can serve as potential therapeutic targets to address numerous unmet medical needs1,2.

Pim-1 specific as well as pan-PIM specific inhibitors could be of therapeutic value. Hits from the ZoBio library have been identified using TINS and validated using a kinase inhibition assay. The crystal structure of PIM1 has been solved in partnership with Crelux (Germany) and successful soaking studies have been performed for 37 fragments as shown here. All resources are in place to begin immediate structure-based hit-to-lead studies.


References:

  1. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nawijn, Nat. Rev. Cancer, 2011
  2. Potential Use of Selective and Nonselective Pim Kinase Inhibitors for Cancer Therapy, Drygin, J. Med. Chem., 2012.

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