Structure–activity relationship study of novel quinazoline-based 1,6-naphthyridinones as MET inhibitors with potent antitumor efficacy

As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives w...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2020-12, Vol.208, p.112785-112785, Article 112785
Main Authors: Zhuo, Lin-Sheng, Wu, Feng-Xu, Wang, Ming-Shu, Xu, Hong-Chuang, Yang, Fan-Peng, Tian, Yan-Guang, Zhao, Xing-E., Ming, Zhi-Hui, Zhu, Xiao-Lei, Hao, Ge-Fei, Huang, Wei
Format: Article
Language:English
Subjects:
1,6-naphthyridone
Antitumor
MET kinase Inhibitor
Quinazoline
Structure-activity relationship
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Summary:As a privileged scaffold, the quinazoline ring is widely used in the development of EGFR inhibitors, while few quinazoline-based MET inhibitors are reported. In our ongoing efforts to develop new MET-targeted anticancer drug candidates, a series of quinazoline-based 1,6-naphthyridinone derivatives were designed, synthesized, and evaluated for their biological activities. The preliminary SARs studies indicate that the quinazoline scaffold was also acceptable for the block A of class II MET inhibitors. The further pharmacokinetic studies led to the identification of the most promising compound 22a with favorable in vitro potency (MET, IC50 = 9.0 nM), human microsomal metabolic stability (t1/2 = 621.2 min) and oral bioavailability (F = 42%). Moreover, 22a displayed good in vivo antitumor efficacy (IR of 81% in 75 mg/kg) in MET-positive human glioblastoma U-87 MG xenograft model. These positive results indicated that 22a is a potential new MET-targeted antitumor drug lead, which is worthy of further development. [Display omitted] •Quinazoline-based 1,6-naphthyridinones was identified as new MET inhibitor.•Lead compound 22a displayed favorable potency, PK profile and antitumor efficacy.•The quinazoline was a valuable scaffold for the discovery of novel MET inhibitors.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2020.112785