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

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-06-22 DOI:10.1007/s11030-025-11259-7

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

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引用次数: 0

Abstract

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 ALK^G1202R mutation. Ultimately, compound B11, which contains a thiadiazole structure, shows promising activity (ALK^L1196M IC₅₀ = 5.57 nM; ALK^wt IC₅₀ = 9.19 nM; ALK^G1202R IC₅₀ = 15.6 nM).

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新型ALK激酶抑制剂噻二唑衍生物的设计、合成及抗肿瘤活性研究。

近年来，alk阳性NSCLC患者数量增加，同时出现了各种耐药突变。为解决ALK突变引起的耐药问题，本研究以克唑替尼为先导化合物，对其侧链进行修饰，设计合成了一系列含有噻二唑结构的化合物。通过酪氨酸激酶抑制实验和细胞实验对化合物进行评价。结果表明，化合物B11对NSCLC NCI-H2228细胞株具有较强的细胞毒活性。此外，B11表现出剂量依赖效应，抑制NCI-H2228细胞活力，诱导G0/ g1期细胞周期阻滞，促进细胞死亡。更重要的是，化合物B11克服了ALKG1202R突变引起的抗性。最终，含有噻二唑结构的化合物B11显示出良好的活性(ALKL1196M IC50 = 5.57 nM；ALKwt IC50 = 9.19 nM；ALKG1202R IC50 = 15.6 nM)。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;