Yao Keke, Li Yaxin, Wei Wei, Liu Sisi, Wang Xiaoli, Xu Jiamin, Zhang Ranran, Wu Zhigang, Guo Chunyan, Yang Leifu, Hu Liming
College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China.
College of Chemistry and Life Science, Beijing University of Technology, Beijing 100124, China; Hebei Key Laboratory of Neuropharmacology, School of Pharmacy, Hebei North University, Zhangjiakou 075000, China.
Bioorg Med Chem Lett. 2025 Jul 1;122:130214. doi: 10.1016/j.bmcl.2025.130214. Epub 2025 Mar 29.
Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related mortality worldwide. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and the role of epigenetic modifications, such as histone deacetylation, in cancer progression underscore the need for novel therapeutic strategies. This study reports the design, synthesis, and biological evaluation of novel 4-arylaminoquinoline derivatives as dual inhibitors targeting EGFR and histone deacetylase (HDAC). Leveraging structure-activity relationship insights, a series of compounds were synthesized by integrating pharmacophoric elements of EGFR-TKIs and HDAC inhibitors and their kinase and cellular activities were evaluated. Compound 22c2 exhibited the highest inhibitory activities against EGFR (IC = 4.81 nM) and HDAC (IC = 119.4 nM and 354.8 nM for HDAC1 and HDAC3, respectively). Moreover, 22c2 demonstrated excellent anti-proliferative effects on four human cancer cell lines. These findings provide a foundation for developing dual EGFR/HDAC inhibitors as potential anticancer therapeutics.
肺癌，尤其是非小细胞肺癌（NSCLC），仍然是全球癌症相关死亡的主要原因。对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）的耐药性以及表观遗传修饰（如组蛋白去乙酰化）在癌症进展中的作用凸显了新型治疗策略的必要性。本研究报告了新型4-芳基氨基喹啉衍生物作为靶向EGFR和组蛋白去乙酰化酶（HDAC）的双重抑制剂的设计、合成及生物学评价。利用构效关系的见解，通过整合EGFR-TKIs和HDAC抑制剂的药效基团合成了一系列化合物，并对其激酶和细胞活性进行了评估。化合物22c2对EGFR表现出最高的抑制活性（IC = 4.81 nM），对HDAC（HDAC1和HDAC3的IC分别为119.4 nM和354.8 nM）也有较高抑制活性。此外，22c2对四种人类癌细胞系表现出优异的抗增殖作用。这些发现为开发双重EGFR/HDAC抑制剂作为潜在的抗癌治疗药物奠定了基础。
