ATP-phosphopeptide conjugates as inhibitors of Src tyrosine kinases

Authors

Nguyen Hai Nam, University of Rhode Island
Sungsoo Lee, University of Rhode Island
Guofeng Ye, College of Pharmacy
Gongqin Sun, University of Rhode Island
Keykavous Parang, College of Pharmacy

Document Type

Article

Date of Original Version

11-15-2004

Abstract

ATP-phosphopeptide conjugates were synthesized and evaluated in vitro against c-Src and Lck. A number of Src SH2 domain inhibitors enhance the kinase catalytic activity by switching the closed inactive to the open active conformation. ATP-phosphopeptide conjugates were designed and synthesized as Src tyrosine kinase inhibitors based on a tetrapeptide sequence pTyr-Glu-Glu-Ile (pYEEI) and ATP to block the SH2 domain signaling and substrate phosphorylation by ATP, respectively. In general, ATP-phosphopeptide conjugates with optimal linkers such as compounds 5 and 7 (K i = 1.7-2.6 μM) showed higher binding affinities to the ATP-binding site relative to the other ATP-phosphopeptide conjugates having short or long linkers, 1-4 and 6, (K i = 10.1-16.1 μand ATP (K m = 74 μM). These ATP-phosphopeptide conjugates may serve as novel templates for designing protein tyrosine kinase inhibitors to block SH2 mediated protein-protein interactions and to counter the activation of enzyme that resulted from the SH2 inhibition. © 2004 Elsevier Ltd. All rights reserved.

Publication Title, e.g., Journal

Bioorganic and Medicinal Chemistry

Volume

12

Issue

22

Citation/Publisher Attribution

Nam, Nguyen Hai, Sungsoo Lee, Guofeng Ye, Gongqin Sun, and Keykavous Parang. "ATP-phosphopeptide conjugates as inhibitors of Src tyrosine kinases." Bioorganic and Medicinal Chemistry 12, 22 (2004). doi: 10.1016/j.bmc.2004.08.043.