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

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

Dencoda, LLC, West Lafayette, IN 47906, USA

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)

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Abstract

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. View Full-Text

Keywords: 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. https://doi.org/10.3390/molecules24152764

AMA Style

Kim D, Sun Y, Xie D, Denton KE, Chen H, Lin H, Wendt MK, Post CB, Krusemark CJ. Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library. Molecules. 2019; 24(15):2764. https://doi.org/10.3390/molecules24152764

Chicago/Turabian Style

Kim, Dongwook, Yixing Sun, Dan Xie, Kyle E. Denton, Hao Chen, Hang Lin, Michael K. Wendt, Carol B. Post, and Casey J. Krusemark. 2019. "Application of a Substrate-Mediated Selection with c-Src Tyrosine Kinase to a DNA-Encoded Chemical Library" Molecules 24, no. 15: 2764. https://doi.org/10.3390/molecules24152764

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

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