Discovery of 2-Amino-7-Amide Quinazoline Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Extracellular Signal-Regulated Kinase 1/2
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 <b>23</b> 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 <b>23</b> dose-dependently suppressed the phosphorylation of the downstream substrate RSK. Remarkably, <b>23</b> exerted favorable ADMET and PK profiles, as well as significant <i>in vivo</i> antitumor efficacy with excellent tolerance. Collectively, this work offers a novel and highly promising candidate targeting ERK1/2 for further drug development.
Authors
- Ai Zeng
- Shiyang Shen (ORCID: https://orcid.org/0009-0007-8895-7788)
- Wenjuan Zhou (ORCID: https://orcid.org/0000-0001-6762-9303)
- Junyu Xu (ORCID: https://orcid.org/0000-0002-1911-3553)
- Yanyan Chen (ORCID: https://orcid.org/0000-0002-6048-6685)
- Shaopo Deng (ORCID: https://orcid.org/0000-0001-8185-3854)
- Yubo Zhou (ORCID: https://orcid.org/0000-0002-0694-3697)
- Yu He (ORCID: https://orcid.org/0000-0001-7434-5309)
- Yuping Sun (ORCID: https://orcid.org/0000-0003-2477-285X)
- Yi Li (ORCID: https://orcid.org/0000-0001-6024-9973)
- Ping Li (ORCID: https://orcid.org/0000-0002-4926-3835)
- Yu Zhang (ORCID: https://orcid.org/0009-0007-2951-6536)
- Huanhuan Liu (ORCID: https://orcid.org/0000-0003-1790-3073)
- Xiang Cao (ORCID: https://orcid.org/0000-0003-1973-2861)
- Chongli Zhong (ORCID: https://orcid.org/0000-0002-4724-5545)
- Ye Tan
- Peili Zhang
- Zian Zhang (ORCID: https://orcid.org/0000-0002-1907-1402)
Institutions
- Chinese Academy of Sciences (CN)
- Shanghai Institute of Materia Medica (CN)
- Drug Discovery Laboratory (Norway) (NO)
- University of Chinese Academy of Sciences (CN)
- Southern Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01055
- Citations
- 1
- Primary Topic
- Quinazolinone synthesis and applications
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Science and Technology Commission of Shanghai Municipality
- Zhongshan Science and Technology Bureau
- Basic and Applied Basic Research Foundation of Guangdong Province