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Macrocyclization in the design of non-phosphorus-containing Grb2 SH2 domain-binding ligands
Zhen-Dan Shi1, Chang-Qing Wei, Kyeong Lee
1Laboratory of Medicinal Chemistry, CCR, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Abstract:
Macrocyclization from the phosphotyrosyl (pTyr) mimetic's beta-position has previously been shown to enhance Grb2 SH2 domain-binding affinity of phosphonate-based analogues. The current study examined the effects of such macrocyclization using a dicarboxymethyl-based pTyr mimetic. In extracellular assays affinity was enhanced approximately 5-fold relative to an open-chain congener. Enhancement was also observed in whole-cell assays examining blockade of Grb2 binding to the erbB-2 protein-tyrosine kinase.
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