To achieve the goals of this project, we have established a research collaboration with the laboratory of Luisa Escobar Hoyos (Yale University). She had uncovered that SMNDC1 functions as a therapeutic target in pancreatic and ovarian cancers by controlling the splicing of a key exon in ERK1, that is responsible for propagating the KRAS signaling pathway. In collaboration with Dr. Escobar Hoyos, we could show our SMNDC1 inhibitors also impact ERK splicing and activity. In vivo, she could show that injecting SMNDC1 inhibitors into xenograft models impairs tumor growth.
With this knowledge on function effects of SMNDC1 inhibition on cancer cells, we set out to chemically improve SMNDC1 inhibitors. We synthesized 85 novel analogs of the SMNDC1 inhibitors and profiled them for their effects on binding of the Tudor domains of SMNDC1 and SMN1 to their cognate demethylated arginine ligands. This enabled us to further improve the potency of the most active compounds to below 200 nM. Even more importantly, these data enabled us to derive clear structure activity relationships and determine pharmacophores for selective binding to SMNDC1 or its close paralog SMN1.
Finally, we profiled two selected SMNDC1 inhibitors against a panel of 864 cancer cell lines in the Broad Institute PRISM assay. This revealed clear cell-line dependent differences, with some cell lines not responsive at the highest concentration tested of 20 uM, while the proliferation of others was impaired at concentrations around 100 nM. It was reassuring to see pancreatic and ovarian cancer cell lines among the responsive models. In addition, we surprisingly identified the responsiveness of Ewing sarcoma cell lines to these compounds.
Finally, we have initiated efforts to further translate this project. We have therefore presented the project to pharma companies, venture capitalists, venture builders and public funding agencies.
