Mechanistic study of PHGDH enzyme inhibition : towards the development of new anticancer drugs

The selective targeting of metabolic differences that allow cancer cells to proliferate appears as a promising strategy to develop novel anticancer agents. In this context, phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the serine synthetic pathway, is a potential target. Our works therefore focused on the development and study of new PHGDH inhibitors. First, α-ketothioamide PHGDH inhibitors were identified and further optimized by chemical modifications. The best inhibitor of the series was also shown to inhibit PHGDH in cell-based models and to decrease cancer progression in vivo. The use of an original photoactivatable diazirine probe together with mutagenesis experiments led to the identification of a new regulatory allosteric site on PHGDH as the putative binding site. In the second part of this thesis, the works focused on the study of disulfiram (DSF), a drug approved for the treatment of chronic alcoholism, as potential anticancer agent. Hence, we demonstrated that the anticancer effect of DSF was, at least in part, due to PHGDH inhibition through disruption of its particular oligomerization state. In conclusion, this work provides a better understanding of PHGDH inhibition and offers new tools to investigate tumor metabolism.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201