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Small‐Molecule Inhibition of the UNC119–Cargo Interaction
Author(s) -
Mejuch Tom,
Garivet Guillaume,
Hofer Walter,
Kaiser Nadine,
Fansa Eyad K.,
Ehrt Christiane,
Koch Oliver,
Baumann Matthias,
Ziegler Slava,
Wittinghofer Alfred,
Waldmann Herbert
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201701905
Subject(s) - myristoylation , kinase , proto oncogene tyrosine protein kinase src , small molecule , chemistry , microbiology and biotechnology , enzyme , biochemistry , biology , phosphorylation
N‐Terminal myristoylation facilitates membrane binding and activity of proteins, in particular of Src family kinases, but the underlying mechanisms are only beginning to be understood. The chaperones UNC119A/B regulate the cellular distribution and signaling of N‐myristoylated proteins. Selective small‐molecule modulators of the UNC119–cargo interaction would be invaluable tools, but have not been reported yet. We herein report the development of the first UNC119–cargo interaction inhibitor, squarunkin A. Squarunkin A selectively inhibits the binding of a myristoylated peptide representing the N‐terminus of Src kinase to UNC119A with an IC 50 value of 10 n m . It binds to UNC119 proteins in cell lysate and interferes with the activation of Src kinase. Our results demonstrate that small‐molecule inhibition of the UNC119–cargo interaction might provide new opportunities for modulating the activity of Src kinases that are independent of direct inhibition of the enzymatic kinase activity.