Discovery of N-(1,3,4-Thiadiazol-2-yl)amide Derivatives as Uncompetitive Inhibitors of 6-Phosphogluconate Dehydrogenase

  • J Med Chem. 2025 Aug 14;68(15):15403-15421. doi: 10.1021/acs.jmedchem.4c03215.
Rong Zhang  1 ,  Mingming Sun  2 ,  Xin Xiao  1 ,  Huiti Li  1 ,  Lulu Jiang  1 ,  Jing Chen  1 ,  Mingzhong Yang  1 ,  Xueying Yao  1 ,  Changliang Shan  2 ,  Lu Zhou  1  3
Affiliations
  • 1. School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China.
  • 3. Quzhou Fudan Institute, Quzhou 324002, China.
PMID: 40742331 DOI: 10.1021/acs.jmedchem.4c03215
Abstract

6-Phosphogluconate dehydrogenase (6PGD) is a crucial enzyme in the pentose phosphate pathway and a promising target for oncotherapy. However, potent 6PGD inhibitors remain limited. Herein, we report a series of N-(1,3,4-thiadiazol-2-yl)amide derivatives as 6PGD inhibitors, via in vitro enzymatic assay-based high-throughput screening and structure-activity relationship analysis. Among them, 19n exhibited significant potency against 6PGD with an IC50 value of 5.1 ± 1.0 μM. Kinetic analysis indicated that 19n was an uncompetitive inhibitor of 6PGD. Further mechanism study revealed that 19n disrupted 6PGD oligomerization in a substrate-dependent manner. Additionally, compound 19n suppressed the proliferation of A549 and Huh7 cells. Moreover, 19n treatment could result in a decrease of NADPH and Ru-5-P production as well as DNA synthesis in A549 cells. Overall, we provide a new scaffold compound 19n which expands the chemical space of 6PGD inhibitors with a novel mechanism and is worthy of further study.

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