蛋白激酶C
细胞生物学
磷酸化
化学
激酶
重编程
酪氨酸激酶
酪氨酸磷酸化
信号转导
生物化学
生物
细胞
作者
Veronika M. Shoba,Dhanushka N. P. Munkanatta Godage,Santosh Kumar Chaudhary,Arghya Deb,Sachini U. Siriwardena,Amit Choudhary
标识
DOI:10.1002/anie.202202770
摘要
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 death of chronic myeloid leukemia cell lines. These studies show the power of synthetic chemistry to expand the chemical and functional diversity of proteins in cells using bifunctional molecules.
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