2. Academic Validation
  3. Discovery of 5-bromo-4-phenoxy-N-phenylpyrimidin-2-amine derivatives as novel ULK1 inhibitors that block autophagy and induce apoptosis in non-small cell lung cancer

Discovery of 5-bromo-4-phenoxy-N-phenylpyrimidin-2-amine derivatives as novel ULK1 inhibitors that block autophagy and induce apoptosis in non-small cell lung cancer

  • Eur J Med Chem. 2020 Dec 15;208:112782. doi: 10.1016/j.ejmech.2020.112782.
Dejuan Sun 1,  Zijian Yang 1,  Yongqi Zhen 2,  Yushang Yang 3,  Yanmei Chen 1,  Yong Yuan 3,  Lan Zhang 4,  Xiaoxi Zeng 5,  Lixia Chen 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China.
  • 2 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China.
  • 3 Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China. Electronic address: zhanglanx_9@126.com.
  • 5 West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: zengxiaoxi@wchscu.cn.
  • 6 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China. Electronic address: syzyclx@163.com.
PMID: 32961380 DOI: 10.1016/j.ejmech.2020.112782
Abstract

UNC51-like kinase1 (ULK1) recruits its binding partners and initiates the Autophagy process in Cancer. ULK1 is significantly overexpressed in Non-small cell lung Cancer (NSCLC) and negatively correlated with clinical prognosis in NSCLC patients. Based upon the binding features of ULK1, we explored the pharmacophore modeling to discover the common anchoring features. It was verified by synthesizing 5-bromo-4-phenoxy-N-phenylpyrimidin-2-amine derivatives, as well as subsequently elucidating the structure-activity relationships (SAR). Among all the obtained ULK1 inhibitors, 5-bromo-4-(2-fluoro-4-nitrophenoxy)-N-(3,4,5-trimethoxyphenyl) pyrimidin-2-amine (3s), was the most active one. The docking analysis was conducted to compare 3s and SBI-0206965, which further elucidated the roles of the H-bond donor. This compound inhibited the proliferation of A549 cells and showed strong inhibitory activity against ULK1 kinase. Moreover, we found that compound 3s could induce Apoptosis while simultaneously blocking Autophagy. Collectively, these findings shed new LIGHT on compound 3s that would be utilized as a promising candidate drug for the future NSCLC therapy.

Keywords

A549 cells; Apoptosis; Autophagy; Non-small cell lung cancer; ULK1 inhibitors.

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