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
  • 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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