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Open AccessArticle

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

1
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
2
Dencoda, LLC, West Lafayette, IN 47906, USA
3
X-Chem Pharmaceuticals, Waltham, MA 02453, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2019, 24(15), 2764; https://doi.org/10.3390/molecules24152764
Received: 24 June 2019 / Revised: 23 July 2019 / Accepted: 26 July 2019 / Published: 30 July 2019
(This article belongs to the Special Issue DNA-Encoded Chemical Libraries)
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 IC50′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. View Full-Text
Keywords: DNA-encoded chemical library; protein tyrosine kinases; substrate-mediated selection; c-Src DNA-encoded chemical library; protein tyrosine kinases; substrate-mediated selection; c-Src
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MDPI and ACS Style

Kim, D.; Sun, Y.; Xie, D.; Denton, K.E.; Chen, H.; Lin, H.; Wendt, M.K.; Post, C.B.; Krusemark, C.J. Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library. Molecules 2019, 24, 2764.

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