7VA1
Crystal structure of human 3-phosphoglycerate dehydrogenase in complex with GDD-04-35
Summary for 7VA1
| Entry DOI | 10.2210/pdb7va1/pdb |
| Descriptor | D-3-phosphoglycerate dehydrogenase, 4-[(3-ethanoylphenyl)sulfamoyl]-~{N}-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]benzamide (3 entities in total) |
| Functional Keywords | oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 93827.75 |
| Authors | |
| Primary citation | Gao, D.,Tang, S.,Cen, Y.,Yuan, L.,Lan, X.,Li, Q.H.,Lin, G.Q.,Huang, M.,Tian, P. Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy. J.Med.Chem., 66:285-305, 2023 Cited by PubMed Abstract: Being the rate-limiting enzyme within the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH) is abnormally overexpressed in numerous malignant tumor cells and is a promising target for cancer treatment. Here, we report a series of novel PHGDH inhibitors using a focused compound screening and structural optimization approach. The lead compound displayed good enzymatic inhibitory activity (IC = 2.8 ± 0.1 μM), high binding affinity ( = 2.33 μM), and sensitivity to the cell lines with the gene amplification or overexpression. Furthermore, was proven to restrict the serine synthesis from glucose within MDA-MB-468 cells. X-ray crystallographic analysis, molecular dynamics simulations, and mutagenesis experiments on PHGDH revealed the binding site at D175 inside the NAD-binding pocket. Finally, exhibited excellent pharmacokinetic properties ( = 82.0%) and exerted evident antitumor efficacy in the PC9 xenograft mouse model. PubMed: 36594670DOI: 10.1021/acs.jmedchem.2c01202 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.74 Å) |
Structure validation
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