Synthetic Reprogramming of Kinases Expands Cellular Activities of Proteins.

ABSTRACT: Phosphorylation-inducing chimeric small molecules (PHICS) can enable a kinase to act at a new cellular location or phosphorylate non-native substrates (neo-substrates)/ sites (neo-phosphorylations).^[1, 2] We report a modular design and high-yielding synthesis of such PHICS that endowed multiple new activities to protein kinase C (PKC). For example, while PKC is unable to downregulate the activity of a gain-of-function variant (S180A) of Bruton's tyrosine kinase that evokes B cell malignancy phenotype, PHICS enabled PKC to induce inhibitory neo-phosphorylations on this variant. Furthermore, while PKC typically phosphorylates its membrane-associated substrates, PKC with PHICS phosphorylated multiple cytosol-based neo-substrates (e.g., BCR-ABL). Finally, a PHICS for BCR-ABL induced

SUBMITTER: Shoba VM 

PROVIDER: S-EPMC9527066 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature