Keke Yao , Yaxin Li , Wei Wei , Sisi Liu , Xiaoli Wang , Jiamin Xu , Ranran Zhang , Zhigang Wu , Chunyan Guo , Leifu Yang , Liming Hu
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引用次数: 0
Abstract
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 (IC50 = 4.81 nM) and HDAC (IC50 = 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.
期刊介绍:
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.