BIOMAT Database Logo BIOMAT Database Logo

Design, synthesis and biological evaluation of novel osimertinib derivatives as reversible EGFR kinase inhibitors. 2022

Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
College of Pharmacy of Liaoning University, 66 Chongshan Road, Huanggu District, Shenyang, 110036, PR China; API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang, 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang, 110036, PR China.

A series of osimertinib derivatives without acrylamide groups were synthesized and their inhibitory rates against L858R/T790M/C797S mutated EGFR kinase and antiproliferation activities against non-small cell lung cancer cell lines (A549, H1975) were evaluated. The preferred compounds were selected and their in vitro inhibitory activities against various EGFR kinases (wild-type, L858R/T790M, L858R/T790M/C797S) and c-Met kinase were tested. Compound 9h showed remarkable inhibitory activity against the wild type (IC50 = 29 nM), L858R/T790M mutant type (IC50 = 10 nM) and L858R/T790M/C797S mutant type (IC50 = 242 nM) as reversible EGFR kinase inhibitor, which was selected to further perform the AO/EB staining assays, cell cycle distribution assays and wound-healing assays on A549 and/or H1975 cell lines. The results showed dose-dependent activities of the induction of cell apoptosis, G1/G0-phase arrestation and inhibition of migration. Compound 22a showed remarkable inhibitory activity against the L858R/T790M/C797S mutant EGFR kinase (IC50 = 137 nM), which was nearly three times compared to osimertinib (IC50 = 410 nM). It's worth noting that 22a exhibited excellent kinase selectivity against the L858R/T790M/C797S mutant EGFR kinase rather than the wild-type, which reached 5.4 times and far more than the 0.012 times of osimertinib. Additionally, molecular docking analyses were performed to explain the action modes between the compounds and the corresponding EGFR kinases. In conclusion, compounds 9h and 22a have been demonstrated as promising candidates and worth further study.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008175 Lung Neoplasms Tumors or cancer of the LUNG. Cancer of Lung,Lung Cancer,Pulmonary Cancer,Pulmonary Neoplasms,Cancer of the Lung,Neoplasms, Lung,Neoplasms, Pulmonary,Cancer, Lung,Cancer, Pulmonary,Cancers, Lung,Cancers, Pulmonary,Lung Cancers,Lung Neoplasm,Neoplasm, Lung,Neoplasm, Pulmonary,Pulmonary Cancers,Pulmonary Neoplasm
D009154 Mutation Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations. Mutations
D011743 Pyrimidines A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.
D002289 Carcinoma, Non-Small-Cell Lung A heterogeneous aggregate of at least three distinct histological types of lung cancer, including SQUAMOUS CELL CARCINOMA; ADENOCARCINOMA; and LARGE CELL CARCINOMA. They are dealt with collectively because of their shared treatment strategy. Carcinoma, Non-Small Cell Lung,Non-Small Cell Lung Cancer,Non-Small Cell Lung Carcinoma,Non-Small-Cell Lung Carcinoma,Nonsmall Cell Lung Cancer,Carcinoma, Non Small Cell Lung,Carcinomas, Non-Small-Cell Lung,Lung Carcinoma, Non-Small-Cell,Lung Carcinomas, Non-Small-Cell,Non Small Cell Lung Carcinoma,Non-Small-Cell Lung Carcinomas
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000178 Acrylamides Colorless, odorless crystals that are used extensively in research laboratories for the preparation of polyacrylamide gels for electrophoresis and in organic synthesis, and polymerization. Some of its polymers are used in sewage and wastewater treatment, permanent press fabrics, and as soil conditioning agents.
D000814 Aniline Compounds Compounds that include the aminobenzene structure. Phenylamine,Phenylamines,Anilines,Compounds, Aniline
D045744 Cell Line, Tumor A cell line derived from cultured tumor cells. Tumor Cell Line,Cell Lines, Tumor,Line, Tumor Cell,Lines, Tumor Cell,Tumor Cell Lines
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein

Related Publications

Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, Synthesis and Biological Evaluation of Novel Osimertinib-Based HDAC and EGFR Dual Inhibitors.
June 2019, Molecules (Basel, Switzerland),
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Synthesis and evaluation of osimertinib derivatives as potent EGFR inhibitors.
September 2017, Bioorganic & medicinal chemistry,
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, Synthesis and Biological Evaluation of Benzohydrazide Derivatives Containing Dihydropyrazoles as Potential EGFR Kinase Inhibitors.
August 2016, Molecules (Basel, Switzerland),
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, synthesis, biological evaluation and docking study of novel quinazoline derivatives as EGFR-TK inhibitors.
April 2021, Future medicinal chemistry,
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors.
January 2010, Bioorganic & medicinal chemistry,
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, synthesis and biological evaluation of 2-phenylaminopyrimidine derivatives as EGFR inhibitors.
February 2024, Bioorganic & medicinal chemistry letters,
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, synthesis, and biological evaluation of novel 4-anilinoquinazoline derivatives bearing amino acid moiety as potential EGFR kinase inhibitors.
April 2017, European journal of medicinal chemistry,
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, synthesis and biological evaluation of quinoxalin-2(1H)-one derivatives as EGFR tyrosine kinase inhibitors.
January 2015, Anti-cancer agents in medicinal chemistry,
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors.
January 2016, Bioorganic & medicinal chemistry letters,
Shi Ding, and Ziye Gao, and Ziqiang Hu, and Rui Qi, and Xiangshan Zheng, and Xiaoyong Dong, and Mingjuan Zhang, and Jiwei Shen, and Tian Long, and Yan Zhu, and Lu Tian, and Wenshan Song, and Ruoqing Liu, and Ying Li, and Jiahuan Sun, and Wenwen Duan, and Ju Liu, and Ye Chen
Design, synthesis and biological evaluation of naphthostyril derivatives as novel protein kinase FGFR1 inhibitors.
February 2015, Journal of enzyme inhibition and medicinal chemistry,
Copied contents to your clipboard!