SPHINX31 is a potent and selective inhibitor of serine/arginine-rich protein kinase 1 (SRPK1), with an IC50 of 5.9 nM. SPHINX31 inhibits phosphorylation of serine/arginine-rich splicing factor 1 (SRSF1). SPHINX31 is a potential topical therapeutic for neovascular eye disease[1].
SRPK1 (serine/arginine-protein kinase 1) regulates splicing of pro-angiogenic VEGFA165a through phosphorylation of SRSF1, enabling SRSF1 nuclear translocation and binding to the proximal splice site in VEGF-A pre-mRNA. SPHINX31 is a highly selective SRPK1 inhibitor with IC50 value of 6nM. Treatment with SPHINX31 dose-dependently inhibited TNFα-induced phosphorylation of SRSF1 (serine/arginine splicing factor 1) mediated by SRPK1 with EC50 value of about 360nM in PC3 prostate cancer cells and switched splicing from VEGF-A165a to VEGF-A165b in RPE cells. SPHINX31 exhibited ocular penetrance and showed anti-angiogenic efficacy as it potently inhibited blood vessel growth in models of wet age-related macular degeneration in vivo when used as eye drops (20 μg/ml) post 14 days. Inhibition of SRPK1 by SPHINX31 halted AML expansion in vitro and in vivo, leading to cell cycle arrest, leukemic cell differentiation, and prolonged survival of immunocompromised mice transplanted with MLL-rearranged AML cells, and affected BRD4 recruitment to chromatin.
作用机制
SPHINX31 occupies a binding pocket created by the unique helical insert of SRPK1 and triggers a backbone flip in the hinge region, resulting potent and selective inhibition of SRPK1 kinase activity.[1]
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