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Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease

Research output: Contribution to journalArticle

  • Jennifer Batson
  • Hamish D. Toop
  • Clara Redondo
  • Roya Babaei-Jadidi
  • Apirat Chaikuad
  • Stephen F. Wearmouth
  • Brian Gibbons
  • Claire Allen
  • Cynthia Tallant
  • Jingxue Zhang
  • Chunyun Du
  • Jules C. Hancox
  • Tom Hawtrey
  • Joana Da Rocha
  • Renate Griffith
  • Stefan Knapp
  • David O. Bates
  • Jonathan C. Morris
Original languageEnglish
Pages (from-to)825-832
Number of pages8
JournalACS Chemical Biology
Volume12
Issue number3
Early online date30 Jan 2017
DOIs
DateAccepted/In press - 30 Jan 2017
DateE-pub ahead of print - 30 Jan 2017
DatePublished (current) - 17 Mar 2017

Abstract

Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity. Treatment with these inhibitors inhibited SRPK1 activity and phosphorylation of serine/arginine splicing factor 1 (SRSF1), resulting in alternative splicing of VEGF-A from pro-angiogenic to antiangiogenic isoforms. This property resulted in potent inhibition of blood vessel growth in models of choroidal angiogenesis in vivo. This work identifies tool compounds for splice isoform selective targeting of pro-angiogenic VEGF, which may lead to new therapeutic strategies for a diversity of diseases where dysfunctional splicing drives disease development.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via ACS at https://doi.org/10.1021/acschembio.6b01048 . Please refer to any applicable terms of use of the publisher.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via ACS at https://doi.org/10.1021/acschembio.6b01048 . Please refer to any applicable terms of use of the publisher.

    Final published version, 1.86 MB, PDF document

    Licence: Other

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