5 years ago

Small-Molecule Inhibition of the UNC119–Cargo Interaction

Small-Molecule Inhibition of the UNC119–Cargo Interaction
Tom Mejuch, Walter Hofer, Eyad K. Fansa, Alfred Wittinghofer, Herbert Waldmann, Guillaume Garivet, Slava Ziegler, Matthias Baumann, Nadine Kaiser, Christiane Ehrt, Oliver Koch
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 IC50 value of 10 nm. 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. Cargo unloading: The first specific small-molecule inhibitor of the interaction between UNC119 proteins and myristoylated cargo, squarunkin A, was developed. Squarunkin A interacts with the hydrophobic pocket of the UNC119 proteins and interferes with the activation of Src kinases.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/anie.201701905

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