SH2 and SH3 domains: potential targets for anti-cancer drug design.
Protein-tyrosine kinases interact with a diverse group of signaling molecules that share common structural elements known as Src homology 2 and 3 (SH2 and SH3) domains. SH2 domains bind with high affinity to peptide sequences within target proteins that contain phosphorylated tyrosine residues, but have no affinity for the unphosphorylated sequence. This property allows activated tyrosine kinases to initiate signal transduction by recruiting downstream effectors with SH2 domains. SH3 domains also mediate protein-protein interaction. Target sequences for SH3 domains are rich in proline and hydrophobic amino acids, but do not require phosphorylation. SH2- and SH3-mediated protein-protein interactions are required for the transmission of proliferative signals initiated by tyrosine kinases (e.g., Ras activation or stimulation of phosphatidylinositol-3' kinase activity). Peptidomimetic ligands based on the sequence of target proteins for SH2 and SH3 domains may represent new lead compounds for the therapy of proliferative diseases that are dependent upon constitutively activated tyrosine kinases (e.g., BCR/ABL in chronic myelogenous and acute lymphocytic leukemias or HER-2/Neu in breast and ovarian cancer.
Smithgall
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Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha 68198-6805, USA.
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents; D015195:Drug Design; D011905:Genes, ras / Q000235:genetics; D008969:Molecular Sequence Data; D010455:Peptides / Q000819:agonists*; D010716:Phosphatidylinositols / Q000737:chemistry; D010766:Phosphorylation; D011392:Proline / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism; D018909:src Homology Domains / Q000502:physiology*
D000970:Antineoplastic Agents; D010455:Peptides; D010716:Phosphatidylinositols; D011392:Proline; D011505:Protein-Tyrosine Kinases; D018631:ras Proteins