Ravez Séverine, Corbet Cyril, Spillier Quentin, Dutu Alice, Robin Anita D, Mullarky Edouard, Cantley Lewis C, Feron Olivier, Frédérick Raphaël
Medicinal Chemistry Research Group (CMFA), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain , 73 avenue Mounier, B-1200 Brussels, Belgium.
Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain , B-1200 Brussels, Belgium.
J Med Chem. 2017 Feb 23;60(4):1591-1597. doi: 10.1021/acs.jmedchem.6b01166. Epub 2017 Jan 27.
Given the putative role of PHGDH in cancer, development of inhibitors is required to explore its function. In this context, we established and validated a straightforward enzymatic assay suitable for high-throughput screening and we identified inhibitors with similar chemical scaffolds. Through a convergent pharmacophore approach, we synthesized α-ketothioamides that exhibit interesting in vitro PHGDH inhibition and encouraging cellular results. These novel probes may be used to understand the emerging biology of this metabolic target.
鉴于磷酸甘油酸脱氢酶（PHGDH）在癌症中的假定作用，需要开发抑制剂来探索其功能。在此背景下，我们建立并验证了一种适用于高通量筛选的直接酶促测定法，并鉴定出具有相似化学骨架的抑制剂。通过收敛药效团方法，我们合成了α-酮硫代酰胺，其在体外表现出有趣的PHGDH抑制作用和令人鼓舞的细胞实验结果。这些新型探针可用于了解这个代谢靶点的新兴生物学特性。
