Signal transduction drug discovery: targets, mechanisms and structure-based design.
Signal transduction targets include catalytic and/or non-catalytic domains, which are critical to various aspects of cell growth, differentiation, metabolism and function, mitogenesis, motility and gene transcription. Specific examples of molecular targets include the catalytic domains of protein tyrosine kinases (PTKs) and of protein tyrosine phosphatases (PTPases), as well as related protein-protein interaction motifs (eg, SH2, PTB and SH3 domains). From the relationship of tyrosine phosphorylation to intracellular pathway regulation by PTKs and PTPases, the dynamic and reversible binding interactions of SH2 and PTB domain-containing proteins with their cognate phosphotyrosine (pTyr)-containing proteins, provide an additional dimension to the modulation of signal transduction pathways which exist as a result of pTyr formation, degradation and molecular recognition events. This review focuses on our current understanding of key relative to recent reports which have provided further insight into their three-dimensional structure and mechanism. This review also highlights recent progress in the design and optimization of molecular mechanism-based signal transduction inhibitors.
Dalgarno
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ARIAD Pharmaceuticals Inc, Cambridge, MA 02139, USA. david.dalgarno@ariad.com
Metcalf
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Shakespeare
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Sawyer
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