A novel class of CLK inhibitors that targets SRSF10 and promote p53-mediated cytotoxicity on human colorectal cancer cells
The expression of the splicing regulator SRSF10 is elevated in metastatic colorectal cancer (CRC) where it promotes the production of the pro-tumorigenic Bclaf1-L splice variant. We discovered a group of small molecules with an aminothiazole carboxamide core (GPS167, GPS192 and others) that decrease production of Bclaf1-L. Additional alternative splicing events regulated by SRSF10 in HCT116 cells were affected by GPS167/192 (e.g. Mdm4 and Wtap), and other events also shifted in a SRSF10-independent manner (e.g. Mdm2, Nab2, Tra2a). GPS167/192 increased the interaction of SRSF10 with CLK1 and CLK4 kinases, leading us to show that GPS167/192 were CLK kinase inhibitors impacting the activity of SRSF10. Notably, GPS167 impaired the growth of colorectal cancer cell lines and organoids, inhibited anchorage-independent colony formation, cell migration and promoted cytoxicity that required SRSF10 and p53. The anti-cancer potential of this new class of CLK kinase inhibitors is further supported by the observation that GPS167 only minimally affected normal colonocytes and normal colorectal organoids. Thus, while SRSF10 promotes tumorigenesis, DNA damage promoted by GPS167 redirects SRSF10 activity towards cell death in a p53-dependent manner. Overall design: Impact of GPS167 or GPS192 on alternative splicing and gene expression profiles of HCT116 cells.