2. Academic Validation
  3. Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors

Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors

  • Bioorg Med Chem. 2024 Feb 1:99:117608. doi: 10.1016/j.bmc.2024.117608.
Yunsheng Xu 1,  Wei Zhao 1,  Xinyi Zhang 1,  Xihua Yu 1,  Yinbo Chen 1,  Zhenghai Wang 1,  Yong Chu 2,  Xueyan Zhu 3,  Peng Zhang 4
Affiliations

Affiliations

  • 1 National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd, China State Institute of Pharmaceutical Industry Co., Ltd., 285 Gebaini Road, Shanghai 201203, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, China.
  • 3 National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd, China State Institute of Pharmaceutical Industry Co., Ltd., 285 Gebaini Road, Shanghai 201203, China. Electronic address: zhuxy001@126.com.
  • 4 National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co., Ltd, China State Institute of Pharmaceutical Industry Co., Ltd., 285 Gebaini Road, Shanghai 201203, China. Electronic address: zhangpeng83@sinopharm.com.
PMID: 38271867 DOI: 10.1016/j.bmc.2024.117608
Abstract

Tropomyosin receptor kinases (TRKs), the superfamily of transmembrane Receptor Tyrosine Kinases, have recently become an attractive method for precision Anticancer therapies since the approval of Larotrectinib and Entrectinib by FDA. Herein, we reported the discovery of a series of novel indazolylaminoquinazoline and indazolylaminoindazole as TRK inhibitors. The representative compound 30f exhibited good inhibitory activity against TRKWT, TRKG595R and TRKG667C with IC50 values of 0.55 nM, 25.1 nM and 5.4 nM, respectively. The compound also demonstrated potent superior to Larotrectinib antiproliferative activity against a panel of Ba/F3 cell lines transformed with both NTRK wild type and mutant fusions (IC50 = 10-200 nM). In addition, compound 30f exhibited good in vitro metabolic stability (T1/2 = 73.0 min), indicating that the quinazoline derivatives may have better metabolic stability. Finally, the binding mode of compound 30f predicted by molecular docking well explained the good Enzyme inhibitory activity of indazolylaminoquinazoline compounds as Trk Inhibitor. Thus, compound 30f can be used as a promising lead molecule for further structural optimization.

Keywords

Indazolylaminoquinazoline; Metabolic stability; Molecular docking; Scaffold hopping; Tropomyosin receptor kinase inhibitors.

Figures
Products
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