Phosphoglycerate dehydrogenase (PHGDH) inhibitors: a comprehensive review 2015–2020

ABSTRACT

Introduction:The phosphoglycerate dehydrogenase (PHGDH), a metabolic enzyme involved in the serine synthetic pathway (SSP), appears to play a central role in supporting cancer growth and proliferation. PHGDH is a dehydrogenase whose expression in cancers was first demonstrated in 2010. Because its silencing allows a significant reduction in tumor proliferation, it appears to be a promising target in the development of new anti-cancer agents.

Areas covered: In this review, we will detail PHGDH inhibitors that were reported since 2015. These compounds will be ranked according to their chemical class and their site of action. Representative examples of each series will be presented as well as their inhibitory potency in vitro and/or in vivo. Finally, their most significant biological effects will be detailed.

Expert opinion: Currently, and despite significant efforts, the search for PHGDH inhibitors has not yet led to the development of compounds that can be used therapeutically. The available inhibitors have either too weak inhibitory potency or limited selectivity. Therefore, it seems crucial, given the importance of this enzyme in the progression of cancer but also in other pathologies, to pursue the development of new chemical series.

KEYWORDS:

• Serine synthetic pathway
• targeted therapies
• cancer metabolism
• phosphoglycerate dehydrogenase

Article highlights

• PHGDH, the main enzyme of the serine synthetic pathway, is overexpressed in numerous cancer types and has been reported to play a key role in cancer cell proliferation.

• The first in vivo data for PHGDH inhibition was reported in 2016 and spurred the development of PHGDH inhibitors for anti-cancer therapies.

• This article discusses the structure and properties of eight allosteric and four orthosteric series of inhibitors published and/or patented since 2015.

• Representative compounds of each series are detailed with structure–activity relationships, mechanism of action (when available) and limitations.

• Besides the field of cancer, PHGDH inhibitors are promising for the treatment of Alzheimer’s disease and cardiovascular diseases.

This box summarizes key points contained in the article.

Declaration of interest

Q. Spillier is a postdoctoral research fellow from Wallonie-Bruxelles International (WBI). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received funding from Wallonie-Bruxelles International (WBI), a J. Maisin Foundation grant, the Fondatioun Kriibskrank Kanner (Luxembourg), a Crédit de Recherche (CDR) grant from the F.R.S.-FNRS, an Action de Recherche Concertée (ARC 14/19-058) grant from the Fédération Wallonie-Bruxelles, and the Télévie.