DESIGN, SYNTHESIS, AND COCRYSTAL STRUCTURE OF A NONPEPTIDE SRC SH2 DOMAIN LIGAND

The specific association of an SH2 domain with a phosphotyrosine (pTyr )-containing sequence of another protein precipitates a cascade of int racellular molecular interactions (signals) which effect a wide range of intracellular processes. The nonreceptor tyrosine kinase Src, which has been associated with breast cancer and osteoporosis, contains an SH2 domain. Inhibition of Src SH2-phosphoprotein interactions by small . molecules will aid biological proof-of-concept studies which may lea d to the development of novel therapeutic agents. Structure-based desi gn efforts have focused on reducing the size and charge of Src SH2 lig ands while increasing their ability to penetrate cells and reach the i ntracellular Src SH2 domain target. In this report we describe the syn thesis, binding affinity, and Src SH2 cocrystal structure of a small, novel, nonpeptide, urea-containing SH2 domain ligand.