Pim-1 is a serine/threonine kinase that has been implicated in the progression of several cancers, including prostate cancer and various leukemias. Using X-ray co-crystallography of small, "scaffold-like" molecules with Pim-1, several new classes of chemical scaffolds that will be the basis for the development of a Pim-1 specific inhibitor will be identified. By focusing on structure and using X-ray co-crystallography as a screen at the earliest stage of lead discovery, it will be possible to directly discover novel scaffolds for Pim-1 that will be the foundation for a potent, selective Pim-1 inhibitor. The structural understanding of the scaffold: protein complex at the outset of the discovery process will be invaluable in identifying key objectives and focusing synthetic chemistry efforts in an efficient manner. The feasibility and utility of scaffold discovery for Pim-1 will be demonstrated by the successful completion of the proposed 20 co-crystal structures and the subsequent improvements in potency and selectivity observed for the 80-100 synthesized compounds. The scaffolds and compounds identified here will be the basis for the eventual identification of a Pim-1 inhibitor as a preclinical candidate for cancer therapy
