2. Academic Validation
  3. Identification of benzo[b]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors

Identification of benzo[b]thiophene-1,1-dioxide derivatives as novel PHGDH covalent inhibitors

  • Bioorg Chem. 2024 May:146:107330. doi: 10.1016/j.bioorg.2024.107330.
Xin-Yu Cao 1,  Xinge Li 2,  Feng Wang 1,  Yichen Duan 3,  Xingmei Wu 1,  Guo-Qiang Lin 1,  Meiyu Geng 4,  Min Huang 5,  Ping Tian 6,  Shuai Tang 7,  Dingding Gao 8
Affiliations

Affiliations

  • 1 The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264100, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264100, China.
  • 6 The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: tianping@shutcm.edu.cn.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai 264100, China. Electronic address: tangshuai@simm.ac.cn.
  • 8 The Research Center of Chiral Drugs, Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine,Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: gaodingding@shutcm.edu.cn.
PMID: 38579615 DOI: 10.1016/j.bioorg.2024.107330
Abstract

The increased de novo serine biosynthesis confers many advantages for tumorigenesis and metastasis. Phosphoglycerate dehydrogenase (PHGDH), a rate-limiting Enzyme in serine biogenesis, exhibits hyperactivity across multiple tumors and emerges as a promising target for Cancer treatment. Through screening our in-house compound library, we identified compound Stattic as a potent PHGDH inhibitor (IC50 = 1.98 ± 0.66 µM). Subsequent exploration in structural activity relationships led to the discovery of compound B12 that demonstrated the increased enzymatic inhibitory activity (IC50 = 0.29 ± 0.02 μM). Furthermore, B12 exhibited robust inhibitory effects on the proliferation of MDA-MB-468, NCI-H1975, HT1080 and PC9 cells that overexpress PHGDH. Additionally, using a [U-13C6]-glucose tracing assay, B12 was found to reduce the production of glucose-derived serine in MDA-MB-468 cells. Finally, mass spectrometry-based peptide profiling, mutagenesis experiment and molecular docking study collectively suggested that B12 formed a covalent bond with Cys421 of PHGDH.

Keywords

Antitumor; Covalent inhibitor; PHGDH; Serine synthesis pathway; Stattic.

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