2. Academic Validation
  3. Design of a covalent protein-protein interaction inhibitor of SRPKs to suppress angiogenesis and invasion of cancer cells

Design of a covalent protein-protein interaction inhibitor of SRPKs to suppress angiogenesis and invasion of cancer cells

  • Commun Chem. 2024 Jun 27;7(1):144. doi: 10.1038/s42004-024-01230-2.
Gongli Cai 1,  Yishu Bao 2,  Qingyun Li 1 3,  Pang-Hung Hsu 4 5 6,  Jiang Xia 2,  Jacky Chi Ki Ngo 7 8 9 10
Affiliations

Affiliations

  • 1 School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
  • 2 Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
  • 3 College of Food Science and Engineering, Henan University of Technology, Zhengzhou, 450001, China.
  • 4 Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan.
  • 5 Center of Excellence for the Oceans, National Taiwan Ocean University, Keelung, Taiwan.
  • 6 Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan.
  • 7 School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. jackyngo@cuhk.edu.hk.
  • 8 Center for Soybean Research of the State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. jackyngo@cuhk.edu.hk.
  • 9 Center of Novel Biomaterials, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. jackyngo@cuhk.edu.hk.
  • 10 Center for Protein Science and Crystallography, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China. jackyngo@cuhk.edu.hk.
PMID: 38937565 DOI: 10.1038/s42004-024-01230-2
Abstract

Serine-arginine (SR) proteins are splicing factors that play essential roles in both constitutive and alternative pre-mRNA splicing. Phosphorylation of their C-terminal RS domains by SR protein kinases (SRPKs) regulates their localization and diverse cellular activities. Dysregulation of phosphorylation has been implicated in many human diseases, including cancers. Here, we report the development of a covalent protein-protein interaction inhibitor, C-DBS, that targets a lysine residue within the SRPK-specific docking groove to block the interaction and phosphorylation of the prototypic SR protein SRSF1. C-DBS exhibits high specificity and conjugation efficiency both in vitro and in cellulo. This self-cell-penetrating inhibitor attenuates the phosphorylation of endogenous SR proteins and subsequently inhibits the angiogenesis, migration, and invasion of Cancer cells. These findings provide a new foundation for the development of covalent SRPK inhibitors for combatting diseases such as Cancer and viral infections and overcoming the resistance encountered by ATP-competitive inhibitors.

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