2. Academic Validation
  3. Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations

Conformational Constrained 4-(1-Sulfonyl-3-indol)yl-2-phenylaminopyrimidine Derivatives as New Fourth-Generation Epidermal Growth Factor Receptor Inhibitors Targeting T790M/C797S Mutations

  • J Med Chem. 2022 May 12;65(9):6840-6858. doi: 10.1021/acs.jmedchem.2c00168.
Hao Chen 1,  Mengzhen Lai 2 3,  Tao Zhang 2,  Yuqing Chen 1,  Linjiang Tong 2,  Sujie Zhu 4,  Yang Zhou 1,  Xiaomei Ren 5,  Jian Ding 2 6,  Hua Xie 2 7 6,  Xiaoyun Lu 1,  Ke Ding 1 5
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 and the 1st Affiliated Hospital (Huaqiao Hospital), 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 Department of Pharmacology, School of Pharmacy, Fudan University, #826 Zhangheng Road, Shanghai 201203, China.
  • 4 Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao 266021, China.
  • 5 State Key Laboratory of Bioorganic and Nature Product Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.
  • 6 University of Chinese Academy of Sciences, #19 Yuquan Road, Beijing 100049, China.
  • 7 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Cuiheng New District, Zhongshan 528400, China.
PMID: 35446588 DOI: 10.1021/acs.jmedchem.2c00168
Abstract

Tertiary C797S mutation of epidermal growth factor receptor (EGFR)-mediated resistance in non-small-cell-lung-cancer (NSCLC) patients is still an unmet clinical need. Several classes of adenosine 5'-triphosphate-competitive or allosteric EGFRT790M/C797S inhibitors and degraders have been developed, but none of them have received approval from the regulatory agencies. Herein, we report the structure-based design of conformational constrained 4-(1-ethylsufonyl-3-indolyl)-2-phenylaminopyrimidines as new EGFRT790M/C797S inhibitors by using a macrocyclization strategy. Representative compound 18j potently inhibited EGFR19del/T790M/C797S and EGFRL858R/T790M/C797S mutants with IC50 values of 15.8 and 23.6 nM and suppressed Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFR19del/T790M/C797S cells with IC50 values of 0.036 and 0.052 μM, respectively, which is 10-20-fold more potent than brigatinib. 18j also potently inhibited the EGFR19del/T790M/C797S-mutated PC-9-OR NSCLC cell proliferation with an IC50 value of 0.644 μM but was less potent for parental Ba/F3 and A431 cells. This study provides a new lead compound for drug discovery to combat EGFRC797S-mediated resistance in NSCLC patients.

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