title: Development of Potent, Selective SRPK1 Inhibitors as Potential Topical Therapeutics for Neovascular Eye Disease.
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.
authors.affiliation: Exonate Ltd , Unit 23, Cambridge Science Park, Cambridge, United Kingdom.|Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham , Queen's Medical Centre, Nottingham NG2 7UH, United Kingdom.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Batson
authors.affiliation: Exonate Ltd , Unit 23, Cambridge Science Park, Cambridge, United Kingdom.|School of Chemistry, UNSW Australia , Sydney, Australia.
authors.forename: Hamish D
authors.identifier: 0000-0003-4637-4764
authors.initials: HD
authors.lastname: Toop
authors.affiliation: Structural Genomic Consortium, University of Oxford , Old Road Campus, Oxford OX3 7DQ, United Kingdom.
authors.forename: Clara
authors.initials: C
authors.lastname: Redondo
authors.affiliation: Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham , Queen's Medical Centre, Nottingham NG2 7UH, United Kingdom.
authors.forename: Roya
authors.initials: R
authors.lastname: Babaei-Jadidi
authors.affiliation: Structural Genomic Consortium, University of Oxford , Old Road Campus, Oxford OX3 7DQ, United Kingdom.|Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University , D-60438, Frankfurt am Main, Germany.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: School of Chemistry, UNSW Australia , Sydney, Australia.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Wearmouth
authors.affiliation: Exonate Ltd , Unit 23, Cambridge Science Park, Cambridge, United Kingdom.
authors.forename: Brian
authors.initials: B
authors.lastname: Gibbons
authors.affiliation: Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham , Queen's Medical Centre, Nottingham NG2 7UH, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Allen
authors.affiliation: Structural Genomic Consortium, University of Oxford , Old Road Campus, Oxford OX3 7DQ, United Kingdom.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Tallant
authors.affiliation: School of Chemistry, UNSW Australia , Sydney, Australia.
authors.forename: Jingxue
authors.initials: J
authors.lastname: Zhang
authors.affiliation: School of Physiology and Pharmacology and Neuroscience, University of Bristol , BS8 1TD, Bristol, United Kingdom.
authors.forename: Chunyun
authors.initials: C
authors.lastname: Du
authors.affiliation: School of Physiology and Pharmacology and Neuroscience, University of Bristol , BS8 1TD, Bristol, United Kingdom.
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.affiliation: School of Chemistry, UNSW Australia , Sydney, Australia.
authors.forename: Tom
authors.initials: T
authors.lastname: Hawtrey
authors.affiliation: School of Chemistry, UNSW Australia , Sydney, Australia.
authors.forename: Joana
authors.initials: J
authors.lastname: Da Rocha
authors.affiliation: School of Medical Sciences, UNSW Australia , Sydney, Australia.
authors.forename: Renate
authors.identifier: 0000-0001-7739-5686
authors.initials: R
authors.lastname: Griffith
authors.affiliation: Structural Genomic Consortium, University of Oxford , Old Road Campus, Oxford OX3 7DQ, United Kingdom.|Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University , D-60438, Frankfurt am Main, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Exonate Ltd , Unit 23, Cambridge Science Park, Cambridge, United Kingdom.|Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham , Queen's Medical Centre, Nottingham NG2 7UH, United Kingdom.
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.affiliation: School of Chemistry, UNSW Australia , Sydney, Australia.
authors.forename: Jonathan C
authors.identifier: 0000-0002-5109-9069
authors.initials: JC
authors.lastname: Morris
mesh_terms: D060433:Administration, Ophthalmic; D020256:Choroidal Neovascularization / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; C087728:SRPK1 protein, human; D017346:Protein Serine-Threonine Kinases