Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Chemical Society
2017
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| _version_ | 1797086768794697728 |
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| author | Batson, J Toop, HD Redondo, ACC Babaei-Jadidi, R Chaikuad, A Wearmouth, SF Gibbons, B Allen, C Tallant, C Zhang, J Du, C Hancox, JC Hawtrey, T Da Rocha, J Griffith, R Knapp, S Bates, DO Morris, JC |
| author_facet | Batson, J Toop, HD Redondo, ACC Babaei-Jadidi, R Chaikuad, A Wearmouth, SF Gibbons, B Allen, C Tallant, C Zhang, J Du, C Hancox, JC Hawtrey, T Da Rocha, J Griffith, R Knapp, S Bates, DO Morris, JC |
| author_sort | Batson, J |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T02:26:42Z |
| format | Journal article |
| id | oxford-uuid:a5da418c-3a92-4789-8ab0-0f9412424a3d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:26:42Z |
| publishDate | 2017 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:a5da418c-3a92-4789-8ab0-0f9412424a3d2022-03-27T02:43:21ZDevelopment of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye diseaseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a5da418c-3a92-4789-8ab0-0f9412424a3dEnglishSymplectic Elements at OxfordAmerican Chemical Society2017Batson, JToop, HDRedondo, ACCBabaei-Jadidi, RChaikuad, AWearmouth, SFGibbons, BAllen, CTallant, CZhang, JDu, CHancox, JCHawtrey, TDa Rocha, JGriffith, RKnapp, SBates, DOMorris, JCSerine/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. |
| spellingShingle | Batson, J Toop, HD Redondo, ACC Babaei-Jadidi, R Chaikuad, A Wearmouth, SF Gibbons, B Allen, C Tallant, C Zhang, J Du, C Hancox, JC Hawtrey, T Da Rocha, J Griffith, R Knapp, S Bates, DO Morris, JC Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease |
| title | Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease |
| title_full | Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease |
| title_fullStr | Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease |
| title_full_unstemmed | Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease |
| title_short | Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease |
| title_sort | development of potent selective srpk1 inhibitors as potential topical therapeutics for neovascular eye disease |
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