3-phosphoglycerate dehydrogenase (PHGDH) inhibitors
- 详细技术说明
- The inventors have identified inhibitors for an enzyme, PHGDH, that is required for the synthesis of serine, which can be used to treat certain cancers.
- *Abstract
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TechnologyOverview
Serine is an essential amino acid required for performing numerousfunctions in the cell, such as the synthesis of lipids that are found in cellmembranes and the synthesis of nucleotides. Serine can be imported from theextracellular space via amino acid transporters, or can be synthesized fromglucose via the phosphoserine pathway. A key enzyme required for the latterprocess is the NAD+ dependent enzyme PHGDH.
It has been well established thatserine synthesis is enhanced in cancer cells, thus contributing to enhancednucleotide synthesis. Focal amplifications of the gene encoding for PHGDH hasbeen shown to occur in breast cancers and melanomas. In triple negative breastcancer and NSCLC, PHGDH amplification and overexpression is associated withmore aggressive forms of the disease. However, the difference between thosecells that largely rely on the import of extracellular serine vs. those thatare addicted to serine synthesis has not yet been established.
The inventors have performed ahigh-throughput screen of a library of 800,000 compounds using an in vitro PHGDH assay and have identifiedlead compounds that are active in cells. These inhibitors selectively inhibitedthe proliferation of melanoma and breast cancer cell lines, but had no effecton lines that relied on extracellular serine uptake. The inhibitors work via anon-competitive mechanism, showed time dependent onset of inhibition anddisrupted the oligomerization state of PHGDH.
Potential Applications
· These inhibitors can be used as compounds to study thebiology of de novo serine synthesis
· PHGDH inhibitors can be used to selectively treat cancersthat depend on serine synthesis for their proliferation (such as breast cancerand melanoma)
Advantages
PHGDH represents a new clinical targetfor cancer treatment and PHGDH inhibitors could provide much-needed therapeuticoptions for the treatment of certain aggressive cancers.
- *Licensing
- Brian J. Kelly, Directorbjk44@cornell.edu646-962-7045
- 其他
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Identification of a smallmolecule inhibitor of 3-phosphoglycerate dehydrogenase to target serinebiosynthesis in cancers. Mullarky et al., PNAS 2016.
- 国家/地区
- 美国
