Phosphorylation-Inducing Chimeric Small Molecules
| Autor: | Stuart L. Schreiber, Veronika Shoba, Peng Wu, Sachini U. Siriwardena, Mengchao Shi, Sophia Lai, Dhanushka N P Munkanatta Godage, Santosh K. Chaudhary, Amit Choudhary |
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| Rok vydání: | 2020 |
| Předmět: |
Gene isoform
Cell signaling Molecular Structure Kinase Chemistry General Chemistry 010402 general chemistry 01 natural sciences Biochemistry Small molecule Catalysis 0104 chemical sciences Cell biology Small Molecule Libraries Colloid and Surface Chemistry Phosphorylation Target protein Tyrosine kinase Protein kinase C |
| Zdroj: | Journal of the American Chemical Society. 142(33) |
| ISSN: | 1520-5126 |
| Popis: | Small molecules have been classically developed to inhibit enzyme activity; however, new classes of small molecules that endow new functions to enzymes via proximity-mediated effect are emerging. Phosphorylation (native or neo) of any given protein-of-interest can alter its structure and function, and we hypothesized that such modifications can be accomplished by small molecules that bring a kinase in proximity to the protein-of-interest. Herein, we describe phosphorylation-inducing chimeric small molecules (PHICS), which enable two example kinases-AMPK and PKC-to phosphorylate target proteins that are not otherwise substrates for these kinases. PHICS are formed by linking small-molecule binders of the kinase and the target protein, and exhibit several features of a bifunctional molecule, including the hook-effect, turnover, isoform specificity, dose and temporal control of phosphorylation, and activity dependent on proximity (i.e., linker length). Using PHICS, we were able to induce native and neo-phosphorylations of BRD4 by AMPK or PKC. Furthermore, PHICS induced a signaling-relevant phosphorylation of the target protein Bruton's tyrosine kinase in cells. We envision that PHICS-mediated native or neo-phosphorylations will find utility in basic research and medicine. |
| Databáze: | OpenAIRE |
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