Can small molecular inhibitors that stop de novo serine synthesis be used in cancer treatment?

Megan Mcnamee, David Michod, Maria Niklison Chirou

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To sustain their malignancy, tumour cells acquire several metabolic adaptations such as increased oxygen, glucose, glutamine, and lipids uptake. Other metabolic processes are also enhanced as part of tumour metabolic reprogramming, for example, increased serine metabolism. Serine is a non-essential amino acid that supports several metabolic processes that are crucial for the growth and survival of proliferating cells, including protein, DNA, and glutathione synthesis. Indeed, increased activity of D-3-phosphoglycerate dehydrogenase (PHGDH), the enzyme rate-limiting de novo serine synthesis, has been extensively reported in several tumours. Therefore, selective inhibition of PHGDH may represent a new therapeutic strategy for over-expressing PHGDH tumours, owing to its downstream inhibition of essential biomass production such as one-carbon units and nucleotides. This perspective article will discuss the current status of research into small molecular inhibitors against PHGDH in colorectal cancer, breast cancer, and Ewing’s sarcoma. We will summarise recent studies on the development of PHGDH-inhibitors, highlighting their clinical potential as new therapeutics. It also wants to shed a light on some of the key limitations of the use of PHGDH-inhibitors in cancer treatment which are worth taking into account.
Original languageEnglish
Article number87
JournalCell Death Discovery
Issue number1
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
We are grateful to Dr. Ivano Amelio for his helpful advice. This work was funded by a Children with Cancer UK fellowship (No. 2014-178), Barts Charity (No. MGU0473), and Life Sciences Institute Fellowship Seed Award-QMUL awarded to M.V.N.-C. and grant W1075E from Great Ormond Street Hospital Children’s Charity awarded to D.M.

Publisher Copyright:
© 2021, The Author(s).

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research


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