Small-Molecule Inhibition of the UNC-Src Interaction Impairs Dynamic Src Localization in Cells
| Autor: | Guillaume Garivet, Philippe I. H. Bastiaens, Alfred Wittinghofer, Herbert Waldmann, Rania Alsaabi, Nadine Kaiser, Tom Mejuch, Antonios D. Konitsiotis, Walter Hofer, Christian Klein, Eyad K. Fansa |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Clinical Biochemistry Biology 01 natural sciences Biochemistry Protein–protein interaction Small Molecule Libraries Mice Drug Discovery Animals Humans Molecular Biology Cells Cultured Adaptor Proteins Signal Transducing Myristoylation Pharmacology Molecular Structure 010405 organic chemistry Cell growth Drug discovery Autophosphorylation Small molecule 0104 chemical sciences Cell biology src-Family Kinases Molecular Medicine Female Tyrosine kinase Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Cell Chemical Biology |
| Popis: | Summary Interference with the signaling activity of the N-myristoylated nonreceptor protein tyrosine kinase Src is considered a viable approach in anti-cancer drug discovery. However, ATP-competitive Src inhibitors have not reached the clinic yet and alternative approaches are in high demand. The UNC119A/B proteins bind the myristoylated N terminus of Src and thereby mediate energy-driven spatial cycles that maintain Src enrichment at the plasma membrane, which is critical for Src signaling activity. We describe the discovery of a potent and specific inhibitor of the UNC119-Src interaction with unprecedented chemotype. The inhibitor binds to UNC119 in cells, and induces redistribution of Src to endomembranes and reduction of activating Src autophosphorylation on Y419. UNC119 inhibition in Src-dependent colorectal cancer cells results in the specific reduction of cell growth and clonogenic potential. Our results demonstrate that small-molecule interference with the dynamics of the Src spatial cycle may provide an opportunity to impair oncogenic Src signaling. |
| Databáze: | OpenAIRE |
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