TY  - JOUR
A1  - Batson, Jennifer
A1  - Toop, Hamish D.
A1  - Redondo, Clara
A1  - Babaei-Jadid, Roya
A1  - Chaikuad, Apirat
A1  - Wearmouth, Stephen F.
A1  - Gibbons, Brian
A1  - Allen, Claire
A1  - Tallant, Cynthia
A1  - Zhang, Jingxue
A1  - Du, Chunyun
A1  - Hancox, Jules C.
A1  - Hawtrey, Tom
A1  - Rocha, Joana Pinto da
A1  - Griffith, Renate
A1  - Knapp, Stefan
A1  - Bates, David O.
A1  - Morris, Jonathan C.
T1  - Development of potent, selective SRPK1 inhibitors as potential topical therapeutics for neovascular eye disease
T2  - ACS chemical biology
N2  - 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.
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/43726
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-437264
SN  - 1554-8929
SN  - 1554-8937
N1  - ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. http://pubs.acs.org/page/policy/authorchoice_termsofuse.html
VL  - 12
IS  - 3
SP  - 825
EP  - 832
PB  - American Chemical Society
CY  - Washington, DC
ER  -