Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library

Molecules

Yixing Sun¹  Hang Lin¹  MichaelK. Wendt¹  Hao Chen¹  Dongwook Kim¹  KyleE. Denton¹  CaseyJ. Krusemark¹  CarolBeth Post¹  Dan Xie¹ 

[1] Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA;

关键词: DNA-encoded chemical library;    protein tyrosine kinases;    substrate-mediated selection;    c-Src;   

DOI  :  10.3390/molecules24152764

来源: DOAJ

【 摘 要 】

As aberrant activity of protein kinases is observed in many disease states, these enzymes are common targets for therapeutics and detection of activity levels. The development of non-natural protein kinase substrates offers an approach to protein substrate competitive inhibitors, a class of kinase inhibitors with promise for improved specificity. Also, kinase activity detection approaches would benefit from substrates with improved activity and specificity. Here, we apply a substrate-mediated selection to a peptidomimetic DNA-encoded chemical library for enrichment of molecules that can be phosphorylated by the protein tyrosine kinase, c-Src. Several substrates were identified and characterized for activity. A lead compound (SrcDEL10) showed both the ability to serve as a substrate and to promote ATP hydrolysis by the kinase. In inhibition assays, compounds displayed IC_50′s ranging from of 8−100 µM. NMR analysis of SrcDEL10 bound to the c-Src:ATP complex was conducted to characterize the binding mode. An ester derivative of the lead compound demonstrated cellular activity with inhibition of Src-dependent signaling in cell culture. Together, the results show the potential for substrate-mediated selections of DNA-encoded libraries to discover molecules with functions other than simple protein binding and offer a new discovery method for development of synthetic tyrosine kinase substrates.

【 授权许可】

Unknown