2. Academic Validation
  3. Discovery of 2-Amino-7-Amide Quinazoline Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Extracellular Signal-Regulated Kinase 1/2

Discovery of 2-Amino-7-Amide Quinazoline Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Extracellular Signal-Regulated Kinase 1/2

  • J Med Chem. 2025 Jun 12;68(11):12204-12228. doi: 10.1021/acs.jmedchem.5c01055.
Peili Zhang 1 2,  Yu Zhang 2,  Yuelan Sun 1 2,  Yanyan Chen 1 2,  Xiang Cao 2,  Yu He 2,  Ye Tan 2,  Zian Zhang 3 4,  Shengyi Deng 3 4,  Wenjuan Zhou 2,  Chuhai Zhong 2,  Ai Zeng 2,  Huanhuan Liu 2,  Jun-Yu Xu 2 3,  Yubo Zhou 2 3,  Shiyang Shen 1 2 3 4,  Ping Li 2 3,  Yi Li 1 2 3 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 2 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China.
  • 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
PMID: 40370105 DOI: 10.1021/acs.jmedchem.5c01055
Abstract

Aberrant activation of the ERK/MAPK pathway is closely associated with various cancers. Directly targeting ERK1/2, the most distal node of this cascade, is not only a rational therapeutic approach for cancers harboring pathway-activating alterations, but also provides a potential solution for overcoming resistance from upstream signaling. Herein, we described the discovery of potent and orally bioavailable ERK1/2 inhibitors featuring 2-amino-7-amide quinazoline skeletons through structure-based drug design. Among them, the optimal compound 23 inhibited ERK1/2 at single-digital nanomolar concentrations with good specificity, and exhibited great potencies in preventing cell growth, migration and invasion, disrupting cell cycle, and inducing cell Apoptosis. Further mechanism studies demonstrated that 23 dose-dependently suppressed the phosphorylation of the downstream substrate RSK. Remarkably, 23 exerted favorable ADMET and PK profiles, as well as significant in vivo antitumor efficacy with excellent tolerance. Collectively, this work offers a novel and highly promising candidate targeting ERK1/2 for further drug development.

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