This technology includes a family of inhibitors of 3-phosphoglycerate dehydrogenase (PHGDH) which could be utilized as a treatment for cancer. These compounds are based on a carbiothioamide core and represent the first chemotype capable of inhibiting this enzyme. The compounds have in vitro IC50s of 1-5 uM and exhibit selective cytotoxicity towards PHGDH-overexpressing cell lines of ~10 uM. They exhibit at least an order of magnitude lower toxicity towards cell lines that do not express PHGDH. These compounds block flux through the serine synthesis pathway in PHGDH-overexpressing cells, and preliminarily appear to do the same in mice.
First chemotype capable of inhibiting 3-phosphoglycerate dehydrogenase.