Discovery and Development of Novel Inhibitors of the Metabolic Enzyme Glycine Decarboxylase as Anticancer Therapeutics

Metabolic pathways in cancer and novel treatment therapies against metabolic targets have emerged recently as a new frontier in metabolic medicine and biomedical therapeutics. GLDC is a key mediator in the glycine-serine pathway catalysing the decarboxylation of the amino acid glycine. GLDC is overexpressed in many cancers including lung, liver and breast cancers and GLDC knockdown in tumor cells leads to a dramatic reduction of tumor growth in mouse models. In patients, aberrant upregulation of GLDC is significantly associated with higher mortality. These links between glycine metabolism and tumorigenesis, support GLDC as a novel anti-cancer target for advancing anti-cancer therapy. We propose an integrated ‘cancer metabolism’ platform for the discovery of small molecule inhibitors against GLDC. Our goal is to demonstrate proof of concept for GLDC inhibition in cancer through small molecule inhibitors and develop those inhibitors into novel, orally active compounds with a strong patent position. We propose to optimize initial hit compounds using advanced assays: enzyme inhibitory potency, specificity, cellular activity, drug-like properties, in vivo pharmacokinetics and in vivo efficacy. We propose to obtain the first X-ray structure of GLDC to aid computational inhibitor design. Our preliminary work has identified 18 structurally distinct chemical series as hit compounds from a GLDC screen combining use of a yeast system and a GLDC-specific enzyme assay. This preliminary work has taken the project significantly further forward into an exciting area. This proposal seeks resources to capitalize on these discoveries. GLDC inhibitors will open up an entirely new area of glycine-serine pathway inhibitor therapy. Further resource will be sought at a later date to translate an optimized compound into the clinic as a huge step not only for ‘joined-up’ Singaporean R&D but for patients and their families.