Spillier Quentin, Ravez Séverine, Unterlass Judith, Corbet Cyril, Degavre Charline, Feron Olivier, Frédérick Raphaël
Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, 1200 Brussels, Belgium.
Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain, 1200 Brussels, Belgium.
Pharmaceuticals (Basel). 2020 Jan 22;13(2):20. doi: 10.3390/ph13020020.
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.
多年来，针对癌细胞代谢失调进行靶向治疗已成为开发更具特异性和高效性癌症治疗方法的一种有前景的策略。最近，大量报道强调了丝氨酸合成途径的关键作用，尤其是该途径的首个酶——磷酸甘油酸脱氢酶（PHGDH）在维持癌症进展中的作用。然而，由于在基于细胞的环境中通常效力非常弱，迄今为止报道的抑制剂未能基于这种方法的潜力取得进展。在本文中，我们报告了对我们最近鉴定的一系列α-酮硫代酰胺的构效关系研究。有趣的是，这项研究使我们对该系列中的构效关系（SAR）有了更深入的理解，并鉴定出了新的PHGDH抑制剂。更有效化合物的活性通过细胞热位移分析和基于细胞的实验得到了证实。我们希望这项研究最终能基于这个有前景的化学支架，为开发靶向PHGDH的治疗药物提供一个新的切入点。
