Identification of a novel PHGDH covalent inhibitor by chemical proteomics and phenotypic profiling

• Published in: Acta pharmaceutica Sinica. B Vol. 12; no. 1; pp. 246 - 261
• Main Authors: Chen, Chen, Zhu, Tianyu, Liu, Xiaoqin, Zhu, Dongrong, Zhang, Yi, Wu, Sifang, Han, Chao, Zhang, Hao, Luo, Jianguang, Kong, Lingyi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2022; Elsevier
• Subjects: Chemical proteomics; Colon cancer; Covalent inhibitor; Original; Oxidative stress; Phosphoglycerate dehydrogenase; Serine synthesis pathway; Withangulatin A; Withanolides; NADPH; Oxidative stress; 3-PG; CETSA; Colon cancer; PSAT; SBD; MD; Serine synthesis pathway; Covalent inhibitor; 3-PHP; PHGDH; GSH; RMSF; DARTS; RMSD; Phosphoglycerate dehydrogenase; Chemical proteomics; SSP; Withangulatin A; Withanolides; CuAAC; ROS; TBTA; TCEP; BLI; ABPP; GSH, glutathione; PSAT, phosphoserine aminotransferase; 3-PHP, 3-phosphohydroxypyruvate; CuAAC, copper-catalyzed alkyne–azide cycloaddition; MD, molecular dynamics; TBTA, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine; DARTS, drug affinity responsive target stability; 3-PG, 3-phosphoglycerate; ROS, reactive oxygen species; BLI, biolayer interferometry assay; PHGDH, phosphoglycerate dehydrogenase; RMSD, root mean square deviation; ABPP, affinity-based protein profiling; CETSA, cellular thermal shift assay; SBD, substrate-binding domain; RMSF, root mean square fluctuations; NADPH, nicotinamide adenine dinucleotide phosphate; TCEP, tris(2-carboxyethyl) phosphine; SSP, serine synthesis pathway

The first rate-limiting enzyme of the serine synthesis pathway (SSP), phosphoglycerate dehydrogenase (PHGDH), is hyperactive in multiple tumors, which leads to the activation of SSP and promotes tumorigenesis. However, only a few inhibitors of PHGDH have been discovered to date, especially the coval...