2. Academic Validation
  3. SRPKIN-1: A Covalent SRPK1/2 Inhibitor that Potently Converts VEGF from Pro-angiogenic to Anti-angiogenic Isoform

SRPKIN-1: A Covalent SRPK1/2 Inhibitor that Potently Converts VEGF from Pro-angiogenic to Anti-angiogenic Isoform

  • Cell Chem Biol. 2018 Apr 19;25(4):460-470.e6. doi: 10.1016/j.chembiol.2018.01.013.
John M Hatcher 1,  Guowei Wu 2,  Chuyue Zeng 3,  Jie Zhu 4,  Fan Meng 2,  Sherrina Patel 5,  Wenqiu Wang 5,  Scott B Ficarro 6,  Alan L Leggett 7,  Chelsea E Powell 1,  Jarrod A Marto 6,  Kang Zhang 5,  Jacky Chi Ki Ngo 3,  Xiang-Dong Fu 8,  Tinghu Zhang 9,  Nathanael S Gray 10
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 3 School of Life Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region NA, China.
  • 4 Shiley Eye Institute, Institute for Engineering in Medicine, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
  • 5 Shiley Eye Institute, Institute for Engineering in Medicine, Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • 6 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Oncologic Pathology and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 8 Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
  • 9 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
  • 10 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 29478907 DOI: 10.1016/j.chembiol.2018.01.013
Abstract

The SRPK family of kinases regulates pre-mRNA splicing by phosphorylating serine/arginine (SR)-rich splicing factors, signals splicing control in response to extracellular stimuli, and contributes to tumorigenesis, suggesting that these splicing kinases are potential therapeutic targets. Here, we report the development of the first irreversible SRPK Inhibitor, SRPKIN-1, which is also the first kinase inhibitor that forms a covalent bond with a tyrosine phenol group in the ATP-binding pocket. Kinome-wide profiling demonstrates its selectivity for SRPK1/2, and SRPKIN-1 attenuates SR protein phosphorylation at submicromolar concentrations. Vascular endothelial growth factor (VEGF) is a known target for SRPK-regulated splicing and, relative to the first-generation SRPK Inhibitor SRPIN340 or small interfering RNA-mediated SRPK knockdown, SRPKIN-1 is more potent in converting the pro-angiogenic VEGF-A165a to the anti-angiogenic VEGF-A165b isoform and in blocking laser-induced neovascularization in a murine retinal model. These findings encourage further development of SRPK inhibitors for treatment of age-related macular degeneration.

Keywords

SRPK1/2; SRPKIN-1; VEGF; alternative splicing; irreversible inhibitor.

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