2. Academic Validation
  3. Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors

Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors

  • Eur J Med Chem. 2021 Nov 5:223:113648. doi: 10.1016/j.ejmech.2021.113648.
Daowei Huang 1,  Jixia Yang 2,  Qingwei Zhang 3,  Guan Wang 3,  Zixue Zhang 3,  Yue Zhang 4,  Jianqi Li 5
Affiliations

Affiliations

  • 1 School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China.
  • 2 School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050018, China.
  • 3 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China.
  • 4 School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China. Electronic address: yuezhang02@163.com.
  • 5 Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China. Electronic address: lijianqb@126.com.
PMID: 34175535 DOI: 10.1016/j.ejmech.2021.113648
Abstract

The HGF/Met signaling pathway is over-expressed in many types of cancers and closely related to oncogenesis and metastasis. Thus, we developed novel N-phenylpyrimidin-2-amine derivatives to test their inhibitory activities towards c-Met kinase, and most of the compounds (15a-i, 15o-r, 20 and 34a-c) could inhibit the target with IC50 values from 550.8 nM to 15.0 nM. Subsequently, compound 15b, 15d, 15f, 15i, 15o, 15r, 20, 34a and 34b also showed high antiproliferative activities in c-Met sensitive tumor cell lines (PC-3, Panc-1, HepG2, HCT116 and Caki-1) with IC50 values from 0.53 to 1.37 μM. The lead compound 34a displayed outstanding c-Met inhibitory activity (IC50: 15.0 nM) and antiproliferative activities. Furthermore, 34a also performed favorable pharmacokinetic properties in mice (F%: 59.3) and an acceptable safety profile in preclinical studies. Further docking studies showed a common interaction of 34a with c-Met at the ATP-binding site, which indicated that 34a could be a potential candidate for c-Met inhibitors.

Keywords

Anti-cancer; N-Phenylpyrimidin-2-amine; Synthesis; Tyrosine kinase; c-Met.

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