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<p>In recent years, the number of patients with ALK-positive NSCLC has increased, along with the emergence of various resistance mutations. To address the resistance issues caused by ALK mutations, this study used Crizotinib as the lead compound and modified its side chain to design and synthesize a series of compounds containing thiadiazole structures. The compounds were evaluated through tyrosine kinase inhibition assays and cellular experiments. The results show that compound <b>B11</b> exhibits strong cytotoxic activity against the NSCLC NCI-H2228 cell line. Moreover, <b>B11</b> demonstrates a dose-dependent effect, inhibiting NCI-H2228 cell viability, inducing G0/G1-phase cell cycle arrest, and promoting cell death. More importantly, compound <b>B11</b> overcomes the resistance caused by the ALK<sup>G1202R</sup> mutation. Ultimately, compound <b>B11</b>, which contains a thiadiazole structure, shows promising activity (ALK<sup>L1196M</sup> IC<sub>50</sub> = 5.57&#xa0;nM; ALK<sup>wt</sup> IC<sub>50</sub> = 9.19&#xa0;nM; ALK<sup>G1202R</sup> IC<sub>50</sub> = 15.6&#xa0;nM).</p>

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Design, synthesis and antitumor activity of thiadiazole derivatives as novel ALK kinase inhibitors

  • 期刊论文

  • 发表日期：

    2025年6月22日

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  • Yiwen Huo,
  • Qinjiang Zhou,
  • Cheng Zhang,
  • Yanna Lv,
  • Rongfei Liu,
  • Mingyue Hou,
  • Xiaoxuan Duan,
  • Yue Liu,
  • Jinxing Hu

摘要

In recent years, the number of patients with ALK-positive NSCLC has increased, along with the emergence of various resistance mutations. To address the resistance issues caused by ALK mutations, this study used Crizotinib as the lead compound and modified its side chain to design and synthesize a series of compounds containing thiadiazole structures. The compounds were evaluated through tyrosine kinase inhibition assays and cellular experiments. The results show that compound B11 exhibits strong cytotoxic activity against the NSCLC NCI-H2228 cell line. Moreover, B11 demonstrates a dose-dependent effect, inhibiting NCI-H2228 cell viability, inducing G0/G1-phase cell cycle arrest, and promoting cell death. More importantly, compound B11 overcomes the resistance caused by the ALKG1202R mutation. Ultimately, compound B11, which contains a thiadiazole structure, shows promising activity (ALKL1196M IC50 = 5.57 nM; ALKwt IC50 = 9.19 nM; ALKG1202R IC50 = 15.6 nM).