The SRPK inhibitor N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl) isonicotinamide (SRPIN340) increases the immune response against metastatic melanoma in mice

Impaired expression of serine/arginine protein kinase 2 (SRPK2) affects melanoma progression

“…Several SRPK1/2-related roles in cancer have been reported, such as angiogenesis (Gammons et al, 2014), proliferation (Jang et al, 2008), cell migration and EMT (Wang et al, 2017), metastasis (van Roosmalen et al, 2015Zhuo et al, 2018), lipid biosynthesis (Lee et al, 2017), genome stability maintenance (Sridhara et al, 2017), and drug resistance mediation (Wang et al, 2019). We previously demonstrated the anti-metastatic effect of pharmacological inhibitors targeting the SRPK1/2 family in melanoma (Gammons et al, 2014;Moreira et al, 2018;Moreira et al, 2022). As selective SRPK pharmacological inhibitors are still unknown, the role of SRPK1 or SRPK2 activity in melanoma remains obscure.…”

“…We downloaded clinical and pre-processed single-cell RNA sequencing (scRNA-Seq) public data (Jerby-Arnon et al, 2018) of patients with melanoma and processed it according to the scripts available in the GitHub repository "SRPK at single-cell resolution" (Rapozo and Santos, 2022a). We used the previous annotation of the Seurat object (Butler et al, 2018) to identify all the cells of the tumor microenvironment (TME) (Moreira et al, 2022). Melanoma is largely related to DNA copy number changes (Shain et al, 2015).…”

“…Using the previous classification according to SRPK1/ 2 expression (Moreira et al, 2022), we grouped the clusters of malignant cells that had low expression of SRPK1/2 (0, 2, 3, and 4) in relation to the cluster that had a high percentage of cells expressing SRPK1/2 (1) (Figure 1C, Supplementary Figure S1E,F). We named these clusters as "Low_SRPK" (1,485 cells) and "High_SRPK" (662 cells), respectively.…”

“…SRPIN340 was the first discovered SRPK inhibitor with antiviral potential (Fukuhara et al, 2006). In the tumor context, we have demonstrated that SRPK1/2 pharmacological inhibition by the classical inhibitor SRPIN340 and other derivatives decreased the invasive capacity of metastatic melanoma B16F10 cells in vitro and reduced the formation of pulmonary nodules in vivo, which can be related to immune system activation (Moreira et al, 2018;Mendes et al, 2022;Moreira et al, 2022). However, as SRPIN340 inhibits SRPK1 and to a lesser extent SRPK2, as well other splicing kinases (Fukuhara et al, 2006), these data are limited in informing which SRPK1/ 2 member is relevant for melanoma progression.…”