Insights from Pim1 structure for anti-cancer drug design.

Introduction: Pim1 is a unique, constitutively active serine/threonine kinase, and is a potent oncogene overexpressed in a range of hematologic malignancies and solid cancers. It functions as a signaling regulator in cell proliferation and survival pathways through substrate phosphorylation. More than 400 small molecular Pim1 inhibitors with IC(50)/Ki < 10 μM have been registered in the ChEMBL. However, no drug targeting Pim1 has been launched at this present time. Areas covered: The authors provide a review of Pim1 inhibitors from the viewpoint of the structural analysis of the Pim1-inhibitor complexes. PDB data and PubMed literature searches were performed. The inhibitors have been classified and summarized by their interactions with Pim1 residues, to facilitate desirable inhibitor design. Expert opinion: To obtain a potent and selective Pim1 inhibitor as a lead compound, the authors propose the development of compounds which simultaneously interact with both the ATP binding site (Lys67, Glu121 and Phe49) and substrate binding residues (Asp128, Asp131 and Glu171). The development of Pim1 inhibitors could lead to new therapeutic options for a number of hematological malignancies and prostate cancer in the future.