2. Academic Validation
  3. Discovery of benzimidazo-2-amino-1,3,4-thiadiazole carboxylate small-molecule STAT3 inhibitors for colorectal carcinoma therapy

Discovery of benzimidazo-2-amino-1,3,4-thiadiazole carboxylate small-molecule STAT3 inhibitors for colorectal carcinoma therapy

  • Eur J Med Chem. 2026 Mar 15:306:118588. doi: 10.1016/j.ejmech.2026.118588.
Ru Wang 1,  En-Jia Zhou 2,  Chun-Yu Zhang 2,  Liang-Peng Li 1,  Bei-Bei Yang 1,  Ting-Ting Du 3,  Jing Jin 4,  Li Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Digestive Health, 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 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
  • 4 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Digestive Health, 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. Electronic address: [email protected].
PMID: 41564506 DOI: 10.1016/j.ejmech.2026.118588
Abstract

To identify potent candidate drugs for colorectal Cancer (CRC), a series of N-benzimidazole-1,3,4-thiadiazole-2-amine derivatives featuring diverse ester groups were designed and synthesized, based on our preceding research. Systematic pharmacological evaluation demonstrated their inhibitory effects against the IL-6/JAK/STAT3 signaling pathway and CRC cell lines with constitutively activated STAT3. Among these derivatives, compound L20 demonstrated the most potent anti-proliferative activity against HCT116 (IC50 = 0.45 ± 0.05 μM) and Other CRC-relevant cell lines. Mechanistic investigations confirmed that L20 directly binds to STAT3 protein (KD = 6.16 μM), specifically interacting with its SH2 domain. This binding resulted in a dose-dependent suppression of STAT3 phosphorylation at Y705 without affecting total STAT3 protein levels. Furthermore, L20 dose-dependently downregulated both the transcription and expression of cyclin-D1 and c-Myc, two critical downstream effectors of STAT3. Additionally, it induced cell cycle arrest and promoted Apoptosis in HCT116 cells in a concentration-dependent manner. Notably, in a murine MC38 subcutaneous xenograft model, L20 administration (20 mg/kg, i.p.) significantly suppressed tumor growth, achieving a tumor growth inhibition rate of 59.8 %. These results highlight the promise of L20 as a novel candidate for CRC therapy and establish a compelling basis for the continued develop of STAT3-targeted interventions against CRC.

Keywords

Benzimidazo-1,3,4-thiadiazole carboxylates; Colorectal cancer; STAT3 inhibitor; Targeted therapy.

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