3-phosphoglycerate Dehydrogenase (PHGDH) Inhibitors

Technology Overview

Serine is an essential amino acid required for performing numerous functions in the cell, such as the synthesis of lipids that are found in cell membranes and the synthesis of nucleotides. Serine can be imported from the extracellular space via amino acid transporters, or can be synthesized from glucose via the phosphoserine pathway. A key enzyme required for the latter process is the NAD+ dependent enzyme PHGDH.

It has been well established that serine synthesis is enhanced in cancer cells, thus contributing to enhanced nucleotide synthesis. Focal amplifications of the gene encoding for PHGDH has been shown to occur in breast cancers and melanomas. In triple negative breast cancer and NSCLC, PHGDH amplification and overexpression is associated with more aggressive forms of the disease. However, the difference between those cells that largely rely on the import of extracellular serine vs. those that are addicted to serine synthesis has not yet been established.

The inventors have performed a high-throughput screen of a library of 800,000 compounds using an in vitro PHGDH assay and have identified lead compounds that are active in cells. These inhibitors selectively inhibited the proliferation of melanoma and breast cancer cell lines, but had no effect on lines that relied on extracellular serine uptake. The inhibitors work via a non-competitive mechanism, showed time dependent onset of inhibition and disrupted the oligomerization state of PHGDH.

Potential Applications

• These inhibitors can be used as compounds to study the biology of de novo serine synthesis
• PHGDH inhibitors can be used to selectively treat cancers that depend on serine synthesis for their proliferation (such as breast cancer and melanoma)

Advantages

PHGDH represents a new clinical target for cancer treatment and PHGDH inhibitors could provide much-needed therapeutic options for the treatment of certain aggressive cancers.