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Open AccessArticle

Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

1
Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, 1200 Brussels, Belgium
2
Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, 1200 Brussels, Belgium
3
UMR-S1172—JPArc—Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer, Université de Lille, Inserm, CHU Lille, 59000 Lille, France
4
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 21 Solna, Sweden
*
Author to whom correspondence should be addressed.
These authors equally contributed to the work and share the first authorship position.
Pharmaceuticals 2020, 13(2), 20; https://doi.org/10.3390/ph13020020
Received: 3 December 2019 / Revised: 4 January 2020 / Accepted: 14 January 2020 / Published: 22 January 2020
For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH.
Keywords: PHGDH; α-ketothioamides; serine synthesis pathway inhibitors PHGDH; α-ketothioamides; serine synthesis pathway inhibitors
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MDPI and ACS Style

Spillier, Q.; Ravez, S.; Unterlass, J.; Corbet, C.; Degavre, C.; Feron, O.; Frédérick, R. Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH). Pharmaceuticals 2020, 13, 20.

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