2. Academic Validation
  3. Discovery of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine as an effective molecular skeleton to develop reversible/irreversible pan-HER inhibitors

Discovery of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine as an effective molecular skeleton to develop reversible/irreversible pan-HER inhibitors

  • Eur J Med Chem. 2022 Apr 5;233:114249. doi: 10.1016/j.ejmech.2022.114249.
Qidong Tang 1,  Ting Peng 2,  Jie Hu 1,  Tao Zhang 2,  Pengqin Chen 3,  Daoxing Chen 1,  Yunjie Wang 1,  Lingfeng Chen 4,  Linjiang Tong 2,  Yi Chen 2,  Hua Xie 5,  Guang Liang 6
Affiliations

Affiliations

  • 1 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China.
  • 2 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China.
  • 4 School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, China.
  • 5 Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, China. Electronic address: hxie@simm.ac.cn.
  • 6 Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, 325001, China; School of Pharmacy, Hangzhou Medical College, Hangzhou, 311399, China. Electronic address: wzmcliangguang@163.com.
PMID: 35259690 DOI: 10.1016/j.ejmech.2022.114249
Abstract

Pan-HER inhibitors exhibit extensive biological activity and offer unique advantages and usually bind to targets in an irreversible manner. Owing to the off-target toxicity of irreversible inhibitors, reversible pan-HER inhibitors are desirable. Herein, we describe the process of N-(ring structure fused phenyl)quinazoline-4-amine-based design, synthesis, and biological evaluation of pan-HER inhibitors in vitro and in vivo. Compound C5, with the molecular skeleton of N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine, displayed irreversible binding just like Other effective pan-HER inhibitors. To our surprise, compound C6, which possessed the same skeleton, was found to be a high-strength reversible pan-HER inhibitor. This compound was capable of inhibiting HER1s (such as EGFR T790M/L858R and WT), HER2, and HER4 and can be considered as a breakthrough in the development of pan-HER inhibitors. Altogether, N-(3-bromo-1H-indol-5-yl)-quinazolin-4-amine can serve as an effective molecular skeleton for developing both reversible and irreversible pan-HER inhibitors in the following discovery of antitumor drugs.

Keywords

Anti-tumor; Quinazolin-4-amine derivatives; Reversible/irreversible pan-HER inhibitor; Structure-activity relationship.

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