CO-CRYSTAL STRUCTURES OF LIPID KINASES WITH SMALL MOLECULE INHIBITORS

Stanford University, Stanford CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our goal is to determine high resolution co-crystal structures of protein and lipid kinase therapeutic targets in complex with a series of inhibitors derived from our structure-based scaffold discovery platform. Our research relies heavily on the x-ray diffraction resources at institutions like SSRL in order to elucidate the molecular interactions of small molecule inhibitors in complex with kinase targets. These targets are important in diverse pathophysiological processes, such as tumorigenesis and metastasis. Targeting these enzymes with small molecule inhibitors enables the potential to treat human disease including cancers. For some kinase targets, we are not able to obtain co-crystals larger than 50 ?m which often leads to low-resolution diffraction with conventional x-ray sources. Therefore, access to a micro-focus beam line has the potential to be a valuable new resource for structure-based kinase therapy research.