2. Academic Validation
  3. Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment

Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment

  • J Med Chem. 2023 Sep 14;66(17):12373-12395. doi: 10.1021/acs.jmedchem.3c00863.
Ru Wang 1,  Ting-Ting Du 2,  Wen-Qiang Liu 1,  Yi-Chen Liu 2,  Ya-Dong Yang 1,  Jin-Ping Hu 3,  Ming Ji 2,  Bei-Bei Yang 1,  Li Li 1,  Xiao-Guang Chen 2
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050,China.
  • 2 Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 3 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
PMID: 37594012 DOI: 10.1021/acs.jmedchem.3c00863
Abstract

Signal transducer and activator of transcription 3 (STAT3) is an attractive target for Cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N-(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12, compound 40 was identified as a selective STAT3 Inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC50 value = 2.97 μM) and MDA-MB-231 (IC50 value = 3.26 μM) Cancer cells and induced cell cycle arrest and Apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155982
    99.83%, STAT3抑制剂
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