2. Academic Validation
  3. Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors

Discovery and optimization of 4-anilinoquinazoline derivatives spanning ATP binding site and allosteric site as effective EGFR-C797S inhibitors

  • Eur J Med Chem. 2022 Dec 15;244:114856. doi: 10.1016/j.ejmech.2022.114856.
Dou Dou 1,  Jie Wang 1,  Yunjin Qiao 1,  Gulinuer Wumaier 2,  Wenjie Sha 1,  Wenjie Li 1,  Wenyi Mei 1,  Tingyuan Yang 1,  Chen Zhang 1,  Huan He 1,  Caolin Wang 1,  Linna Chu 1,  Baihui Sun 1,  Rongrong Su 1,  Xiangyu Ma 1,  Mengdie Gong 1,  Lijuan Xie 1,  Wenzhe Jiang 1,  Yanyan Diao 1,  Lili Zhu 1,  Zhenjiang Zhao 1,  Zhuo Chen 3,  Yufang Xu 4,  Shengqing Li 5,  Honglin Li 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
  • 2 Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address: [email protected].
  • 4 Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address: [email protected].
  • 5 Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 6 Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China. Electronic address: [email protected].
PMID: 36279692 DOI: 10.1016/j.ejmech.2022.114856
Abstract

Epidermal growth factor receptor (EGFR) is an effective drug target for the treatment of non-small cell lung Cancer (NSCLC). However, a tertiary point mutation (C797S) at the ATP binding pocket of the EGFR induces resistance to the third-generation EGFR inhibitors, due to the loss of covalent interaction with Cys797. Here, we designed a series of 4-anilinoquinazoline derivatives that simultaneously occupied the ATP binding pocket and the allosteric site. The newly-synthesized compounds displayed high potency against EGFR-C797S resistance mutation. Among them, compound 14d presented high anti-proliferative effect against BaF3-EGFRL858R/T790M/C797S (IC50 = 0.75 μM) and BaF3-EGFR19del/T790M/C797S (IC50 = 0.09 μM) cells. Moreover, 14d resulted in obvious inhibition activities against EGFR and its downstream signaling pathways in a dose-dependent manner in BaF3-EGFR19del/T790M/C797S cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR19del/T790M/C797S xenograft model (30 mg/kg, TGI = 67.95%). These results demonstrated that 14d is a novel and effective EGFR-C797S inhibitor which spanning the ATP binding pocket and the allosteric site and effective both in vitro and in vivo.

Keywords

4-Anilinoquinazoline; Anti-proliferative activity; Epidermal growth factor receptor (EGFR); Kinase inhibitor; Non-small cell lung cancer (NSCLC).

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