Discovery of Potent and Wild-Type-Sparing Fourth-Generation EGFR Inhibitors for Treatment of Osimertinib-Resistance NSCLC

被引：21

作者：

Dong, Haojie ^{[1
,2
]}

Ye, Xiuquan ^{[1
]}

Zhu, Yasheng ^{[1
,2
]}

Shen, Hao ^{[1
]}

Shen, Hongtao ^{[1
,3
]}

Chen, Weijiao ^{[1
,2
]}

Ji, Minghui ^{[1
,2
]}

Zheng, Mingming ^{[1
,2
]}

Wang, Keren ^{[1
,3
]}

Cai, Zeyu ^{[1
,2
]}

Sun, Haopeng ^{[1
,2
]}

Xiao, Yibei ^{[1
,3
,4
]}

Yang, Peng ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Jiangsu Key Lab Drug Design & Optimizat, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Sch Pharm, Dept Med Chem, Nanjing 211198, Peoples R China

[3] China Pharmaceut Univ, Sch Pharm, Dept Pharmacol, Nanjing 211198, Peoples R China

[4] Pharmaceut Univ, Chongqing Innovat Inst China, Chongqing 401135, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 10期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

FACTOR RECEPTOR INHIBITORS; LUNG-CANCER; MANAGEMENT; MUTATIONS; PROGRESS; AZD9291;

D O I：

10.1021/acs.jmedchem.3c00277

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Osimertinib resistance is an unmet clinical need for the treatment of non-small cell lung cancer (NSCLC), and the main mechanism is tertiary C797S mutation of epidermal growth factor receptor (EGFR). To date, there is no inhibitor approved for the treatment of Osimertinib-resistant NSCLC. Herein, we reported a series of Osimertinib derivatives as fourth-generation inhibitors which were rationally designed. Top candidate D51 potently inhibited the EGFR(L858R/T790M/C797S) mutant with an IC50 value of 14 nM and suppressed the proliferation of H1975-TM cells with an IC50 value of 14 nM, which show over 500-fold selectivity against wild-type forms. Moreover, D51 inhibited the EGFR(del19/T790M/C797S) mutant and the proliferation of the PC9-TM cell line with IC50 values of 62 and 82 nM. D51 also exhibited favorable in vivo druggability, including PK parameters, safety properties, in vivo stability, and antitumor activity.

引用

页码：6849 / 6868

页数：20

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