CHEMICAL PROBES FOR STUDYING EUKARYOTIC CELL BIOLOGY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We have developed a structural bioinformatics method for designing highly selective inhibitors of protein kinases. We use a structure-based sequence alignment of the human kinome to identify non-conserved cysteines near or within the ATP binding pocket. We then identify reversible inhibitors that bind with modest affinity and selectivity. We design and synthesize derivatives with electrophilic substituents at positions predicted to be proximal to the non-conserved cysteine. In another project, we have discovered a family of cyclodepsipeptides, termed 'cotransins', which potently inhibit the expression of several pro-inflammatory and pro-angiogenic factors in primary human cells. These compounds act at the endoplasmic reticulum and block the cotranslational translocation of a subset of human secretory proteins. We are currently synthesizing cyclopeptide variants and determining structure-activity relationships.