Citation: Hu Xianglong, Xun Qiuju, Zhang Tao, Zhu Su-Jie, Li Qian, Tong Linjiang, Lai Mengzhen, Huang Tao, Yun Cai-Hong, Xie Hua, Ding Ke, Lu Xiaoyun. 2-Oxo-3, 4-dihydropyrimido[4, 5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant[J]. Chinese Chemical Letters, ;2020, 31(5): 1281-1287. doi: 10.1016/j.cclet.2019.09.044 shu

2-Oxo-3, 4-dihydropyrimido[4, 5-d] pyrimidines as new reversible inhibitors of EGFR C797S (Cys797 to Ser797) mutant

Hu Xianglong ^a,1 ,
Xun Qiuju ^a,1 ,
Zhang Tao ^b,1 ,
Zhu Su-Jie ^c,1 ,
Li Qian ^a ,
Tong Linjiang ^b ,
Lai Mengzhen ^b ,
Huang Tao ^a ,
Yun Cai-Hong ^d,*, ,
Xie Hua ^b,*, ,
Ding Ke ^a,*, ,
Lu Xiaoyun ^a,*,

a.
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE), School of Pharmacy, Jinan University, Guangzhou 510632, China
b.
Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
c.
Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China
d.
Department of Biochemistry and Biophysics, Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China

Received Date: 31 July 2019
Revised Date: 16 September 2019
Accepted Date: 23 September 2019
Available Online: 24 September 2019

Figures(5)

Extensive structure-activity relationships (SARs) study of JND3229 was conducted to yield a series of new reversible 2-oxo-3, 4-dihydropyrimido[4, 5-d]pyrimidine privileged scaffold as EGFR^C797S inhibitors. One of the most potent compound 6i potently suppressed EGFR^{L858R/T790M/C797S} kinase with an IC₅₀ value of 3.1 nmol/L, and inhibited the proliferation of BaF3 cells harboring EGFR^{L858R/T790M/C797S} and EGFR^{19D/T790M/C797S} mutants with IC₅₀ values of 290 nmol/L and 316 nmol/L, respectively. Further, 6i dose-dependently induced suppression of the phosphorylation of EGFR^{L858R/T790M/C797S} and EGFR^{19D/T790M/C797S} in BaF3 cells. Compound 6i may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.
- EGFR^C797S mutant,
- SARs,
- 2-Oxo-3, 4-dihydropyrimido[4, 5-d],
- pyrimidine,
- Clinical resistance,
- Fourth-generation inhibitors
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