2. Academic Validation
  3. Discovery of 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline as a novel c-myc inhibitor against colorectal cancer in vitro and in vivo

Discovery of 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline as a novel c-myc inhibitor against colorectal cancer in vitro and in vivo

  • Eur J Med Chem. 2020 Jul 15:198:112336. doi: 10.1016/j.ejmech.2020.112336.
Jie Yang 1,  Chaoguo Cao 1,  Dan Luo 1,  Suke Lan 2,  Meng Luo 1,  Huifang Shan 1,  Xinyu Ma 1,  Yuanyuan Liu 1,  Su Yu 1,  Xinxin Zhong 1,  Rui Li 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 2 College of Chemistry & Environment Protection Engineering, Southwest Minzu University, Chengdu, 610041, China.
  • 3 State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: lirui@scu.edu.cn.
PMID: 32387836 DOI: 10.1016/j.ejmech.2020.112336
Abstract

Proto-oncogene c-Myc plays an essential role in the development of colorectal Cancer (CRC), since downregulation of c-Myc inhibits intestinal polyposis, which is the most cardinal pathological change in the development of CRC. Herein, a series of novel phenoxy-N-phenylaniline derivatives were designed and synthesized. The cytotoxicity activities of all the derivatives were measured by MTT assay in different colon Cancer cells, 4-(3,5-dimethoxy-4-(((4-methoxyphenethyl)amino)methyl)phenoxy)-N-phenylaniline (42) was discovered, the lead compound 42 with excellent cytotoxicity activity of IC50 = 0.32 μM, IC50 = 0.51 μM, in HT29 and HCT 15 cells, respectively. Compound 42 had a good inhibitory activity of c-Myc/MAX dimerization and DNA binding. Besides, compound 42 could effectively induce Apoptosis and induced G2/M arrest in low concentration and G0/G1 arrest in high concentration to prevent the proliferation and differentiation in colon Cancer cells. Western blot analysis confirmed the 42 strongly down-regulated expression of c-Myc. Furthermore, during 30 days treatment 42 exhibited excellent efficacy in HT29 tumor xenograft model without causing significant weight loss and toxicity. Consequently, 42 could be a promising drug candidate for CRC therapy.

Keywords

Anti-CRC; Colorectal cancer; c-Myc inhibitor.

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