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 phosphotyrosine residues, whereas SH3 domains recognize proline-rich motifs of their interacting partners. SH2 and SH3 domains are frequently found in signaling proteins such as small adaptors and in enzymes such as kinases, lipases and phosphatases, in which they differ from the catalytic motif and constitute recognition modules. SH2 and SH3 domains are also found in oncoproteins and in proteins overexpressed in deregulated signaling pathways in tumor cells. The highly folded structures of these domains have been characterized alone and complexed with the essential fragments of their targets. Therefore, based on molecular data, inhibitors of interactions with SH2 and SH3 domains are considered to be potential antitumor agents. Current results are very promising, as inhibitors with very efficient anti-proliferative activity in tumor cells have been reported. This paper describes SH2 and/or SH3 domain-containing proteins that may constitute targets for anticancer therapeutics. It also deals with the essential structural data concerning SH2 and SH3 domains, and the rational design of inhibitors. Some of the more recent pharmacological results obtained with these compounds are also discussed.
Vidal
M
M
Dèpartement de Pharmacochimie Molèculaire et cellulaire, UMR 8638 CNRS UFR des Sciences Pharmaceutiques et Biologiques, Avenue de l'Observatoire, 75270 Cedex 06, Paris, France.
Gigoux
V
V
Garbay
C
C
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006868:Hydrolysis; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010748:Phosphopeptides / Q000737:chemistry / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics; D011487:Protein Conformation; D015398:Signal Transduction / Q000187:drug effects; D018909:src Homology Domains / Q000187:drug effects*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D008024:Ligands; D009363:Neoplasm Proteins; D010748:Phosphopeptides; D011355:Prodrugs; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases