Tethering small molecules to a phage display library: Discovery of a selective bivalent inhibitor of protein kinase A
Tethering small molecules to a phage display library: Discovery of a selective bivalent inhibitor of protein kinase A
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DOI：
10.1021/ja076197d
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发表时间：
2007-11-14
影响因子：
15
通讯作者：
Ghosh, Indraneel
中科院分区：
文献类型：
--
作者：
Meyer, Scott C.;Shomin, Carolyn D.;Ghosh, Indraneel
We report a noncovalent tethering methodology for the fragment-based selection of bivalent ligands targeting protein kinases. In this approach, a small-molecule warhead, staurosporine, directs a phage display cyclic peptide library to the active site of cAMP-dependent protein kinase (PKA), allowing for targeted library enrichment. A cyclic peptide discovered through this selection, when covalently attached to a staurosporine derivative, displayed a 90-fold increase in affinity for PKA. Moreover, the bivalent inhibitor was shown to be significantly more selective than the starting warhead when tested against a small panel of kinases. Thus our general methodology allows for covalent linkage of known small-molecule ligands to biological libraries for discovering potent bivalent inhibitors of biological targets.
