Antagonists of the Src homology 2 (SH2) domains of Grb2, Src, Lck and ZAP-70.
Src homology 2 (SH2) domains are protein modules that mediate intracellular protein-protein interactions in signal transduction pathways. The specific association of an SH2 domain with a phosphotyrosine-containing sequence of another protein induces a cascade of molecular interactions that effect a wide range of cellular processes. Alterations in these signaling pathways have been associated with the development and progression of a broad range of pathologies. Because of the regulatory role of SH2 domains in these signal transduction pathways, specific SH2 domains can be ideal targets for intervention with therapeutic agents in many different disease indications (e.g. cancer, osteoporosis, disorders of the immune and cardiovascular systems). Among the SH2 domains pursued as drug discovery targets in the last few years are those of Grb2, Src, Lck and ZAP-70. This review focuses on contributions in the design and synthesis of antagonists of these particular SH2 domains. Specific examples have been selected to illustrate how structure-based design approaches have been used to progress in this area of research.
García-Echeverria
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Oncology Research, Novartis Pharma AG, CH-4002, Basel, Switzerland. carlos.garcia-echeverria@pharma.novartis.com
D048868:Adaptor Proteins, Signal Transducing; D015195:Drug Design; D051380:GRB2 Adaptor Protein; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D051746:ZAP-70 Protein-Tyrosine Kinase; D018909:src Homology Domains / Q000187:drug effects*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D011506:Proteins; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases