The SRPK family of kinases regulates pre-mRNA splicing by phosphorylating serine/arginine (SR)-rich splicing factors, signals splicing control in response to extracellular stimuli, and contributes to tumorigenesis, suggesting that these splicing kinases are potential therapeutic targets. Here, we report the development of the first irreversible SRPK inhibitor, SRPKIN-1, which is also the first kinase inhibitor that forms a covalent bond with a tyrosine phenol group in the ATP-binding pocket. Kinome-wide profiling demonstrates its selectivity for SRPK1/2, and SRPKIN-1 attenuates SR protein phosphorylation at submicromolar concentrations. Vascular endothelial growth factor (VEGF) is a known target for SRPK-regulated splicing and, relative to the first-generation SRPK inhibitor SRPIN340 or small interfering RNA-mediated SRPK knockdown, SRPKIN-1 is more potent in converting the pro-angiogenic VEGF-A165a to the anti-angiogenic VEGF-A165b isoform and in blocking laser-induced neovascularization in a murine retinal model. These findings encourage further development of SRPK inhibitors for treatment of age-related macular degeneration.

中文翻译：

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SRPKIN-1：一种共价 SRPK1/2 抑制剂，可有效地将 VEGF 从促血管生成转化为抗血管生成异构体

SRPK 激酶家族通过磷酸化富含丝氨酸/精氨酸 (SR) 的剪接因子来调节前体 mRNA 剪接，信号剪接控制响应细胞外刺激，并有助于肿瘤发生，表明这些剪接激酶是潜在的治疗靶点。在这里，我们报告了第一个不可逆的 SRPK 抑制剂 SRPKIN-1 的开发，它也是第一个与 ATP 结合口袋中的酪氨酸酚基形成共价键的激酶抑制剂。全激酶组分析证明其对 SRPK1/2 的选择性，并且 SRPKIN-1 在亚微摩尔浓度下减弱 SR 蛋白磷酸化。血管内皮生长因子 (VEGF) 是 SRPK 调节剪接的已知靶标，相对于第一代 SRPK 抑制剂 SRPIN340 或小干扰 RNA 介导的 SRPK 敲低，SRPKIN-1 在将促血管生成 VEGF-A165a 转化为抗血管生成 VEGF-A165b 亚型和阻断小鼠视网膜模型中激光诱导的新血管形成方面更有效。这些发现鼓励进一步开发用于治疗年龄相关性黄斑变性的 SRPK 抑制剂。