SH2 and SH3 domains as targets for anti-proliferative agents

The Src homology domains SH2 and SH3 are small modular protein motifs about 100 and 60 amino acids long, respectively. SH2 domains interact with phosp hotyrosine residues, whereas SH3 domains recognize proline-rich motifs of t heir interacting partners. SH2 and SH3 domains are frequently found in sign aling proteins such as small adaptors and in enzymes such as kinases, lipas es and phosphatases, in which they differ from the catalytic motif and cons titute recognition modules. SH2 and SH3 domains are also found in oncoprote ins and in proteins overexpressed in deregulated signaling pathways in tumo r cells, The highly folded structures of these domains have been characteri zed alone and complexed with the essential fragments of their tar.-lets. Th erefore, based on molecular data, inhibitors of interactions with SH2 and S H3 domains are considered to be potential antitumor agents. Current results are very promising, as inhibitors with very efficient anti-proliferative a ctivity in tumor cells have been reported. This paper describes SH2 and/or SH3 domain-containing proteins that may constitute targets for anticancer t herapeutics. It also deals with the essential structural data concerning SH 2 and SH3 domains, and the rational design of inhibitors. Some of the more recent pharmacological results obtained with these compounds are also discu ssed. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.