2. Academic Validation
  3. Design, synthesis and evaluation of azaacridine derivatives as dual-target EGFR and Src kinase inhibitors for antitumor treatment

Design, synthesis and evaluation of azaacridine derivatives as dual-target EGFR and Src kinase inhibitors for antitumor treatment

  • Eur J Med Chem. 2017 Aug 18:136:372-381. doi: 10.1016/j.ejmech.2017.05.006.
Zhishan Cui 1,  Shaopeng Chen 2,  Yanwei Wang 1,  Chunmei Gao 3,  Yuzong Chen 4,  Chunyan Tan 1,  Yuyang Jiang 5
Affiliations

Affiliations

  • 1 The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Antitumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 2 The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Antitumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
  • 4 The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Antitumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; Bioinformatics and Drug Design Group, Department of Pharmacy, Centre for Computational Science and Engineering, 117543, Singapore.
  • 5 The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Antitumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Medicine, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 28525838 DOI: 10.1016/j.ejmech.2017.05.006
Abstract

Overexpression of EGFR is often associated with advanced stage disease and poor prognosis. In certain cancers, Src works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and Src is of therapeutic advantage against these cancers. Based on molecular docking and our previous studies, we rationally designed a new series of azaacridine derivatives as potent EGFR and Src dual inhibitors. Most of the synthesized azaacridines displayed good antiproliferative activity against K562 and A549 cells. The representative compound 13b showed nM IC50 values against K562 and A549 cells, and inhibited EGFR at inhibition rate of 33.53% at 10 μM and Src at inhibition rate of 72.12% at 1 μM. Furthermore, compound 13b could inhibit the expression of EGFR, p-EGFR, Src and p-Src. Moreover, 13b efficiently inhibited the invasion of tumor cells and induced Cancer cells Apoptosis. Our study suggested that azaacridine scaffold can be developed as novel multi-target kinase inhibitors for Cancer therapy.

Keywords

Antitumor; Apoptosis; Azaacridine derivatives; EGFR; Invasion; Src.

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