2. Academic Validation
  3. Design, synthesis and biological evaluation of (E)-4-(2-((1H-indol-5-yl) methylene) hydrazineyl)-5,6,7,8-tetrahydropyrido [4',3':4,5] thieno[2,3-d] pyrimidine derivatives as Arf1-GEFs inhibitors for the treatment of colon cancer

Design, synthesis and biological evaluation of (E)-4-(2-((1H-indol-5-yl) methylene) hydrazineyl)-5,6,7,8-tetrahydropyrido [4',3':4,5] thieno[2,3-d] pyrimidine derivatives as Arf1-GEFs inhibitors for the treatment of colon cancer

  • Eur J Med Chem. 2025 Nov 5:297:117962. doi: 10.1016/j.ejmech.2025.117962.
Ning Li 1,  Chenfei Luo 2,  Yufan Liu 2,  Shaoliang Duan 1,  Xuan Wang 2,  Hua Cheng 1,  Dengqi Xue 1,  Yuetong Wang 2,  Wei Li 1,  Steven X Hou 2,  Liming Shao 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 2 Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Department of Liver Surgery and Transplantation of Liver Cancer Institute at Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
  • 3 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China. Electronic address: limingshao@fudan.edu.cn.
PMID: 40712400 DOI: 10.1016/j.ejmech.2025.117962
Abstract

Arf1, a member of the Ras superfamily of small GTPases, plays a crucial role in lipid metabolism, tumor progression, and immune suppression, making Arf1-GEFs inhibitors attractive targets for Cancer Immunotherapy. However, current Arf1 inhibitors face challenges such as high toxicity and poor solubility. In this study, we report the design, synthesis, and biological evaluation of a series of (E)-4-(2-((1H-indol-5-yl) methylene) hydrazineyl)-5,6,7,8-tetrahydropyrido [4',3':4,5] thieno[2,3-d] pyrimidine derivatives, derived from the lead compound Du102. Rational structural modifications significantly enhanced aqueous solubility while retaining strong Arf1 inhibitory activity. Among these, 18a emerged as a potent Arf1-GEFs inhibitor, effectively promoting CCL5 expression, exhibiting improved in vitro pharmacokinetic properties and demonstrating robust antitumor efficacy in CT26 colon Cancer xenograft models. This study identifies 18a as a promising candidate for colon Cancer Immunotherapy and provides a solid foundation for the development of novel Arf1-GEFs inhibitors with superior pharmacological properties.

Keywords

(E)-hydrazone derivatives of thieno[2,3-d]pyrimidine; Arf1-GEFs inhibitors; Colon cancer immunotherapy; Drosophila-based phenotypic screen.

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