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

Dejuan Sun; Zijian Yang; Yongqi Zhen; Yushang Yang; Yanmei Chen; Yong Yuan; Lan Zhang; Xiaoxi Zeng; Lixia Chen

doi:10.1016/j.ejmech.2020.112782

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. Epub 2020 Aug 29.

Authors

Dejuan Sun¹, Zijian Yang¹, Yongqi Zhen², Yushang Yang³, Yanmei Chen¹, Yong Yuan³, Lan Zhang⁴, Xiaoxi Zeng⁵, Lixia Chen⁶

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Autophagy / drug effects*
Autophagy-Related Protein-1 Homolog / antagonists & inhibitors*
Autophagy-Related Protein-1 Homolog / chemistry
Autophagy-Related Protein-1 Homolog / metabolism
Carcinoma, Non-Small-Cell Lung / drug therapy
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Drug Screening Assays, Antitumor
Humans
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / chemistry
Intracellular Signaling Peptides and Proteins / metabolism
Molecular Docking Simulation
Molecular Structure
Protein Binding
Pyrimidines / chemical synthesis
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Intracellular Signaling Peptides and Proteins
Pyrimidines
Autophagy-Related Protein-1 Homolog
ULK1 protein, human