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Showing results 1 to 6 of 6
  • OER000002575.pdf.jpg
  • Journal article

  • A biophysical framework for double-drugging kinases

    • Authors : Kim, C. (2023)

  • Orthosteric inhibition of kinases has been challenging due to the conserved active site architecture of kinases and emergence of resistance mutants. Simultaneous inhibition of distant orthosteric and allosteric sites, which we refer to as “double-drugging”, has recently been shown to be effective in overcoming drug resistance. However, detailed biophysical characterization of the cooperative nature between orthosteric and allosteric modulators has not be...
  • OER000002753.pdf.jpg
  • Journal article

  • Saturation mutagenesis of a predicted ancestral Syk-family kinase

    • Authors : Hobbs, Helen T. (2023)

  • Many tyrosine kinases cannot be expressed readily in E. coli, limiting facile production of these proteins for biochemical experiments. We used ancestral sequence reconstruction to generate a spleen tyrosine kinase (Syk) variant that can be expressed in bacteria and purified in soluble form, unlike the human members of this family (Syk and ZAP-70). The catalytic activity, substrate specificity, and regulation by phosphorylation of this Syk ...
  • OER000002546.pdf.jpg
  • Industry article

  • Shifting the selectivity of pyrido[2,3-d]pyrimidin-7(8H)-one inhibitors towards the salt-inducible kinase (SIK) subfamily

    • Authors : Rak, Marcel (2023)

  • Salt-inducible kinases 1-3 (SIK1-3) are key regulators of the LKB1-AMPK pathway and play an important role in cellular homeostasis. Dysregulation of any of the three isoforms has been associated with tumorigenesis in liver, breast, and ovarian cancers. We have recently developed the dual pan-SIK/group I p21-activated kinase (PAK) chemical probe MRIA9. However, inhibition of p21-activated kinases has been associated with cardiotoxicity in vivo, w...
  • OER000002982.pdf.jpg
  • Journal article

  • Structure-based design of selective salt-inducible kinase (SIK) inhibitors

    • Authors : Tesch, Roberta (2021)

  • Salt-inducible kinases (SIKs) are key metabolic regulators. Imbalance of SIK function is associated with the development of diverse cancers, including breast, gastric and ovarian cancer. Chemical tools to clarify the roles of SIK in different diseases are, however, sparse and are generally characterized by poor kinome-wide selectivity. Here, we have adapted the pyrido[2,3-d]pyrimidin-7-one-based PAK inhibitor G-5555 for the targeting of SIK, by exploiting differences i...
  • OER000002359.pdf.jpg
  • Journal Article

  • Validity of the cell-extracted proteome as a substrate pool for exploring phosphorylation motifs of kinases

    • Authors : Ishihama, Yasushi (2023)

  • Three representative protein kinases with different substrate preferences, ERK1 (Prodirected), CK2 (acidophilic), and PKA (basophilic), were used to investigate phosphorylation sequence motifs in substrate pools consisting of the proteomes from three different cell lines, MCF7 (human mammary carcinoma), HeLa (human cervical carcinoma), and Jurkat (human acute T-cell leukemia). Specifically, recombinant kinases were added to the cell-extracted proteomes to phosphorylate...