Using insights into Pim1 structure to design new anticancer drugs.

Abstract Human Pim1 (proviral integration site for Moloney murine leukemia virus) kinase is a 313-amino acid serine-threonine kinase that possesses several biological functions in cell survival, proliferation and differentiation, and its overexpression has been observed in a number of human cancers. Indeed, this kinase is a proto-oncogene that has been implicated in early transformation and tumor progression, especially in hematopoietic malignancies and prostate carcinoma where it is a marker of a poor prognosis. For these reasons, Pim1 is emerging as an important target in drug discovery, and many Pim1 inhibitors have been reported in the last three years. The challenge of this research is to obtain compounds that specifically inhibit only Pim1 and not Pim2 and Pim3, the other members of the Pim family, with the aim of providing selective inhibitors as potential therapeutic agents and also of studying the different roles of the three enzymes. In this review Pim1 functions and Pim1 role in human cancer are summarized, but the primary focus of the article is on the Pim1 three-dimensional structure that was deeply analyzed by a detailed inspection of the available crystallographic data and all complexes of small molecule inhibitors reported in the literature to this point. Finally, the use of molecular modeling techniques for the identification and optimization of Pim1 inhibitors is extensively discussed. This data collection, which to the best of our knowledge was not previously reviewed in such detail, could offer a useful tool for medicinal chemists working in the field of small molecule kinase inhibitors.