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

Dou Dou; Jie Wang; Yunjin Qiao; Gulinuer Wumaier; Wenjie Sha; Wenjie Li; Wenyi Mei; Tingyuan Yang; Chen Zhang; Huan He; Caolin Wang; Linna Chu; Baihui Sun; Rongrong Su; Xiangyu Ma; Mengdie Gong; Lijuan Xie; Wenzhe Jiang; Yanyan Diao; Lili Zhu; Zhenjiang Zhao; Zhuo Chen; Yufang Xu; Shengqing Li; Honglin Li

doi:10.1016/j.ejmech.2022.114856

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. Epub 2022 Oct 17.

Authors

Dou Dou¹, Jie Wang¹, Yunjin Qiao¹, Gulinuer Wumaier², Wenjie Sha¹, Wenjie Li¹, Wenyi Mei¹, Tingyuan Yang¹, Chen Zhang¹, Huan He¹, Caolin Wang¹, Linna Chu¹, Baihui Sun¹, Rongrong Su¹, Xiangyu Ma¹, Mengdie Gong¹, Lijuan Xie¹, Wenzhe Jiang¹, Yanyan Diao¹, Lili Zhu¹, Zhenjiang Zhao¹, Zhuo Chen³, Yufang Xu⁴, Shengqing Li⁵, Honglin Li⁶

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: chenzhuo@ecust.edu.cn.
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: yfxu@ecust.edu.cn.
⁵ Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: shengqingli@hotmail.com.
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: hlli@ecust.edu.cn.

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-EGFR^{L858R/T790M/C797S} (IC₅₀ = 0.75 μM) and BaF3-EGFR^{19del/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-EGFR^{19del/T790M/C797S} cells. Finally, 14d significantly inhibited tumor growth in BaF3-EGFR^{19del/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).

MeSH terms

Adenosine Triphosphate / metabolism
Allosteric Site
Aniline Compounds* / chemistry
Aniline Compounds* / pharmacology
Binding Sites
Carcinoma, Non-Small-Cell Lung* / drug therapy
Cell Line, Tumor
Drug Discovery
Drug Resistance, Neoplasm
ErbB Receptors* / antagonists & inhibitors
ErbB Receptors* / genetics
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Mutation
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Quinazolines* / chemistry
Quinazolines* / pharmacology

Substances

Adenosine Triphosphate
anilinoquinazoline
EGFR protein, human
ErbB Receptors
Protein Kinase Inhibitors
Aniline Compounds
Quinazolines