2. Academic Validation
  3. Discovery of 4-((3,4-dichlorophenyl)amino)-2-methylquinolin-6-ol derivatives as EGFR and HDAC dual inhibitors

Discovery of 4-((3,4-dichlorophenyl)amino)-2-methylquinolin-6-ol derivatives as EGFR and HDAC dual inhibitors

  • Eur J Pharmacol. 2023 Oct 18:176114. doi: 10.1016/j.ejphar.2023.176114.
Yuqing Qian 1,  Siyu Zhou 2,  Jiayi Li 3,  Mingyuan Ma 2,  Huanwen Chen 2,  Yin Cao 3,  Yuxiang Zhang 3,  Chaoyu Sun 2,  Kang Li 2,  Yizhao Liu 2,  Shutong Dai 2,  Mingtao Ao 4,  Meijuan Fang 5,  Zhen Wu 6,  Mingdong Li 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, China; Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
  • 2 School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, China.
  • 3 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China.
  • 4 School of Pharmacy, Hubei Engineering Research Center of Traditional Chinese Medicine of South Hubei Province, Hubei University of Science and Technology, Xianning, Hubei, 437100, China. Electronic address: aomingtao@hbust.edu.cn.
  • 5 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: fangmj@xmu.edu.cn.
  • 6 Fujian Provincial Key Laboratory of Innovative Drug Target Research and State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, China. Electronic address: wuzhen@xmu.edu.cn.
  • 7 School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330006, China. Electronic address: 20191005@jxutcm.edu.cn.
PMID: 37863412 DOI: 10.1016/j.ejphar.2023.176114
Abstract

In patients with non-small cell lung Cancer (NSCLC), the standard therapy consists of selective tyrosine kinase inhibitors that target epidermal growth factor receptors (EGFR). Nonetheless, their clinical utility is primarily limited by the development of resistance to drugs. HDAC inhibitors have been shown in studies to reduce the level of EGFR that is expressed and downregulate the EGFR-induced phosphorylation of Akt and ERK. Therefore, dual inhibitors of EGFR and HDAC provide a potential approach as combination treatment synergistically inhibited the growth of NSCLC. Herein, we examined the EGFR inhibition effect of twenty compounds which designed and synthesized by us previously. Among them, compounds 12c and 12d exhibited powerful antiproliferative activity against the NCI-H1975 cell line with IC50 values of 0.48 ± 0.07 and 0.35 ± 0.02 μM, correspondingly. In cell-free kinase assays, both 12c and 12d demonstrated target-specific EGFR inhibition against wild type (EGFRwt). Furthermore, the expression of EGFR and phosphorylation of the EGF-induced pathways were significantly suppressed under the treatment of 12c and 12d. Besides, both histones H3 and H4 exhibited increased levels of acetylation following 12c and 12d treatment. The animal experiments shown that 12d could prevent the growth of tumor, inhibited the expression of EGFR and the phosphorylation levels of p70 S6K, Akt and p38 MAPK in vivo, and did not cause organ damage to the mice during the experiment. Overall, the results illustrated that compound 12c and 12d could serve as effective EGFR and HDAC dual inhibitors in NSCLC cells. Our work offers an alternative strategy for NSCLC therapy.

Keywords

Anticancer drugs; Epidermal growth factor (EGFR); Histone deacetylase (HDAC); Non-small cell lung cancer (NSCLC).

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