2. Academic Validation
  3. Design, synthesis and biological evaluation of new Axl kinase inhibitors containing 1,3,4-oxadiazole acetamide moiety as novel linker

Design, synthesis and biological evaluation of new Axl kinase inhibitors containing 1,3,4-oxadiazole acetamide moiety as novel linker

  • Eur J Med Chem. 2020 Jan 15:186:111867. doi: 10.1016/j.ejmech.2019.111867.
Congjun Xu 1,  Yufei Han 2,  Sicong Xu 2,  Ruxin Wang 2,  Ming Yue 2,  Yu Tian 2,  Xiaofan Li 2,  Yanfang Zhao 3,  Ping Gong 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, PR China. Electronic address: congjunxu@163.com.
  • 2 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China. Electronic address: yanfangzhao@126.com.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning Province, PR China. Electronic address: gongpinggp@126.com.
PMID: 31757525 DOI: 10.1016/j.ejmech.2019.111867
Abstract

Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC50 values ranging from 0.032 to 1.54 μM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC50 = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".

Keywords

1,3,4-Oxadiazole; Axl; Drug resistance; EGFR; Isosteresis.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z