2. Academic Validation
  3. Discovery of 9-arylamino-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline-8-carbonitriles: Potent inducers of immunogenic cell death via colchicine site-targeted microtubule polymerization inhibition

Discovery of 9-arylamino-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline-8-carbonitriles: Potent inducers of immunogenic cell death via colchicine site-targeted microtubule polymerization inhibition

  • Eur J Med Chem. 2026 Apr 5:307:118618. doi: 10.1016/j.ejmech.2026.118618.
Yan Ma 1,  Zhangjian Han 1,  Youyou Feng 2,  Xiangyu Kong 1,  Yabo Wang 1,  Lin Li 1,  Wen Yang 1,  Kehao Yang 1,  Ting Zhang 1,  Zhuang Li 1,  Han Wen 1,  Shuaijia Liu 1,  Yanbo Zheng 3,  Wenjie Guo 3,  Weiwei Niu 4,  Yifan Liu 5,  Kai Zhang 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Hebei Medical University, Shijiazhuang, China.
  • 2 Department of Medicinal Chemistry, Hebei Medical University, Shijiazhuang, China; The Second Hospital of Hebei Medical University, Shijiazhuang, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 4 Department of Medicinal Chemistry, Hebei Medical University, Shijiazhuang, China; The Second Hospital of Hebei Medical University, Shijiazhuang, China. Electronic address: [email protected].
  • 5 Department of Medicinal Chemistry, Hebei Medical University, Shijiazhuang, China. Electronic address: [email protected].
  • 6 Department of Medicinal Chemistry, Hebei Medical University, Shijiazhuang, China. Electronic address: [email protected].
PMID: 41687270 DOI: 10.1016/j.ejmech.2026.118618
Abstract

A series of microtubule polymerization inhibitors that target the colchicine site on the basis of a new scaffold have been developed. Among them, compound 17 exhibited outstanding comprehensive antitumor efficacy against a panel of Cancer cell lines (with an average IC50 value of 17.7 nM). Paclitaxel resistance was successfully overcome in a xenograft model in which paclitaxel-resistant A549/TxR cells were used in BALB/c nude mice, as expected. Moreover, the outstanding antitumor efficacy of compound 17 is attributed not only to its chemical toxicity but also to its ability to induce immunogenic cell death (ICD). In vitro, compound 17 potently induced immunogenic cell death in A549 cells at 80 nM, outperforming the reference drug doxorubicin at 200 nM. In the C57BL/6 mouse LLC model, compound 17 achieved a remarkable 81.6% tumor growth inhibition rate and effectively promoted the infiltration of CD4+ and CD8+ T cells into the tumor microenvironment and increased the levels of multiple serum immune factors. These results highlight 17 as a promising candidate for the development of novel chemoimmunotherapy strategies.

Keywords

Anti-drug resistance; Antitumor efficacy; Colchicine binding site; Immunogenic cell death; Tubulin.

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