2. Academic Validation
  3. Machine-Learning-Driven Discovery of N-Phenylbenzenesulfonamides as a Novel Chemotype for Lactate Dehydrogenase A Inhibition with Anti-Pancreatic Cancer Activity

Machine-Learning-Driven Discovery of N-Phenylbenzenesulfonamides as a Novel Chemotype for Lactate Dehydrogenase A Inhibition with Anti-Pancreatic Cancer Activity

  • J Med Chem. 2025 Jul 24;68(14):14384-14404. doi: 10.1021/acs.jmedchem.5c00359.
Qijie Gong 1 2,  Ying Dong 2,  Jiaqi Liang 1 2,  Jian Zhou 1 2,  Guowei Zhang 3,  Le Yang 1 2,  Tiande Bing 1 2,  Fidiniaina Rina Juliana 1 2,  Ziyuan Zhu 4,  Yue Wu 1 2,  Fulai Yang 2,  Xiang Li 3,  Xiaojin Zhang 1 2
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Department of Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Department of Pharmaceutical Engineering, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Faculties of Pharmacy and Pharmaceutical Sciences, Monash University, Clayton VIC 3800, Australia.
PMID: 40644704 DOI: 10.1021/acs.jmedchem.5c00359
Abstract

Lactate Dehydrogenase A (LDHA) is a promising target for Cancer therapy due to its crucial role in aerobic glycolysis. Despite extensive efforts, the structural diversity of LDHA inhibitors remains limited. Here, we utilized machine learning techniques, particularly reinforcement learning models, along with molecular dynamics simulations and biological validation, to identify N-phenylbenzenesulfonamides as a novel chemotype for LDHA inhibition. Compound 9 was generated and identified as a hit (IC50 = 720 nM), with its sulfonamide moiety forming crucial hydrogen-bonding interactions with LDHA. Structural optimization led to derivatives with enhanced LDHA inhibitory activity, exemplified by compound 28 (IC50 = 156 nM). Compound 28 significantly reduced lactate production and induced Apoptosis in pancreatic Mia PaCa-2 cells and demonstrated robust antitumor effects in vivo following oral administration at 100 mg/kg, with no apparent toxicity observed. These findings position 28 as a promising LDHA inhibitor with a novel chemotype for pancreatic Cancer treatment.

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