Discovery of novel inhibitors of human phosphoglycerate dehydrogenase by activity-directed combinatorial chemical synthesis strategy

• Published in: Bioorganic chemistry 2021-10, Vol.115, p.105159-105159, Article 105159
• Main Authors: Zhou, Xia, Tan, Yuping, Gou, Kun, Tao, Lei, Luo, Yuan, Zhou, Yue, Zuo, Zeping, Sun, Qingxiang, Luo, Youfu, Zhao, Yinglan
• Format: Article
• Language: English
• Subjects: 3-phosphoglycerate dehydrogenase; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Combinatorial chemical synthesis; Combinatorial Chemistry Techniques; DNA Damage - drug effects; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Humans; Inhibitor; Phosphoglycerate Dehydrogenase - antagonists & inhibitors; Phosphoglycerate Dehydrogenase - metabolism; Serine synthesis; Structure-Activity Relationship
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105159

[Display omitted] •We identified novel potent PHGDH inhibitors using high throughput screening.•We used activity-directed combinatorial chemical synthesis to optimize compounds.•b36 inhibited serine synthesis and induced cell cycle arrest in S-phase in vitro. Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay. We adopted activity-directed combinatorial chemical synthesis strategy to optimize this hit compound. Compound b36 was found to be the noncompetitive and the most promising one with IC50 values of 5.96 ± 0.61 μM against PHGDH. Compound b36 inhibited the proliferation of human breast cancer and ovarian cancer cells, reduced intracellular serine synthesis, damaged DNA synthesis, and induced cell cycle arrest. Collectively, our results suggest that b36 is a novel PHGDH inhibitor, which could be a promising modulator to reprogram the serine synthesis pathway and might be a potential anticancer lead worth further exploration.