Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor

Zhong-Rui Li; Feng-Zhi Suo; Bo Hu; Yan-Jia Guo; Dong-Jun Fu; Bin Yu; Yi-Chao Zheng; Hong-Min Liu

doi:10.1016/j.bioorg.2018.11.018

Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor

Bioorg Chem. 2019 Mar:84:164-169. doi: 10.1016/j.bioorg.2018.11.018. Epub 2018 Nov 16.

Authors

Zhong-Rui Li¹, Feng-Zhi Suo¹, Bo Hu¹, Yan-Jia Guo¹, Dong-Jun Fu¹, Bin Yu², Yi-Chao Zheng³, Hong-Min Liu⁴

Affiliations

¹ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Zhengzhou 450001, PR China.
² School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Zhengzhou 450001, PR China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, Jiangsu, PR China. Electronic address: zzuyubin@hotmail.com.
³ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Zhengzhou 450001, PR China. Electronic address: yichaozheng@zzu.edu.cn.
⁴ School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Zhengzhou 450001, PR China. Electronic address: liuhm@zzu.edu.cn.

PMID: 30502627
DOI: 10.1016/j.bioorg.2018.11.018

Abstract

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC₅₀ of 3.98 ± 0.3 μM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting.

Keywords: Inhibitor; Lysine specific demethylase 1; NSCLC; Osimertinib (AZD9291).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrylamides / chemistry
Acrylamides / pharmacology*
Aniline Compounds / chemistry
Aniline Compounds / pharmacology*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Histone Demethylases / antagonists & inhibitors*
Histone Demethylases / pharmacology
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Acrylamides
Aniline Compounds
Antineoplastic Agents
Protein Kinase Inhibitors
osimertinib
Histone Demethylases
KDM1A protein, human