2. Academic Validation
  3. Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S)

Structure-Based Design of 5-Methylpyrimidopyridone Derivatives as New Wild-Type Sparing Inhibitors of the Epidermal Growth Factor Receptor Triple Mutant (EGFRL858R/T790M/C797S)

  • J Med Chem. 2019 Aug 8;62(15):7302-7308. doi: 10.1021/acs.jmedchem.9b00576.
Jiayi Shen 1,  Tao Zhang 2,  Su-Jie Zhu 3,  Min Sun 4,  Linjiang Tong 2,  Mengzhen Lai 2,  Rong Zhang 5,  Wei Xu 1,  Ruibo Wu 5,  Jian Ding 2,  Cai-Hong Yun 6,  Hua Xie 2,  Xiaoyun Lu 1,  Ke Ding 1
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy , Jinan University , 601 Huangpu Avenue West , Guangzhou 510632 , China.
  • 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road , Shanghai 201203 , China.
  • 3 Institute for Translational Medicine, College of Medicine , Qingdao University , Qingdao 266021 , China.
  • 4 Jiangsu Aosaikang Pharmacceutical Co. Ltd. , No. 699 Kejian Road, Jiangsu Science Park , Nanjing 211112 , China.
  • 5 School of Pharmaceutical Sciences , Sun Yat-sen University , Guangzhou 510006 , China.
  • 6 Department of Biochemistry and Biophysics, Institute of Systems Biomedicine, School of Basic Medical Sciences , Peking University Health Science Center , Beijing 100191 , China.
PMID: 31298540 DOI: 10.1021/acs.jmedchem.9b00576
Abstract

Tertiary EGFRC797S mutation induced resistance against osimertinib (1) is an emerging "unmet clinical need" for non-small-cell lung Cancer (NSCLC) patients. A series of 5-methylpyrimidopyridone derivatives were designed and synthesized as new selective EGFRL858R/T790M/C797S inhibitors. A representative compound, 8r-B, exhibited an IC50 of 27.5 nM against the EGFRL858R/T790M/C797S mutant, while being a significantly less potent for EGFRWT (IC50 > 1.0 μM). Cocrystallographic structure determination and computational investigation were conducted to elucidate its target selectivity.

Figures
Products