Design and enzymatic evaluation of new inhibitors of the serine metabolic pathway as potential anticancer agents : structural and functional approach of PHDGH



Cancer is a leading cause of death in the world, especially in developed
countries. These last years, metabolism has emerged as an hallmark of
cancer. Indeed the metabolic reprogramming is a key feature of cancer cells
which allows them to produce the necessary metabolites to their growth.
Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step of the
serine pathway. This reaction diverts the glycolytic 3-phosphoglycerate to
form phosphohydroxypyruvate. The reaction product is then metabolized by
phosphoserine aminotransferase-1 and phosphoserine phosphatase to
generate serine.
Two recent studies have shown that PHGDH is overexpressed in a subset
of melanoma and breast cancer. It has been shown that depleting PHGDH
strongly inhibited the proliferation of cancer cells where PHGDH is
overexpressed making this enzyme an interesting therapeutic target. This
year, new PHGDH inhibitors were reported in three independent
publications showing the growing interest in serine pathway.
The aim of my project is to have a better understanding of the catalytic and
inhibition mechanisms of PHGDH at the molecular level. Crystallography is
the method of choice to achieve this objective. It will be combined with
enzymatic characterizations and mutagenesis to help formation of good
diffracting crystals. Computational modelisation of the enzyme will give a
first overview a full length PHGDH. Finally, screening of an in-house
chemical library will be carried out to discover new fragments binding on
PHGDH, which could lead to new anticancer compounds.
Effective start/end date1/10/1730/09/19