2. Academic Validation
  3. Exploration of novel dihydroquinoxalinone derivatives as EGFRL858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer

Exploration of novel dihydroquinoxalinone derivatives as EGFRL858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer

  • Bioorg Chem. 2023 Jun:135:106494. doi: 10.1016/j.bioorg.2023.106494.
Yu Cao 1,  Xixuan Lu 2,  Liping Fu 3,  Tao Shi 4,  Chong Zhang 4,  Linghui Zeng 4,  Jiankang Zhang 4,  Jiaan Shao 4,  Jianjun Xi 5,  Zongfu Pan 6,  Shourong Liu 7,  Huajian Zhu 8
Affiliations

Affiliations

  • 1 School of Medicine, Zhejiang University City College, Hangzhou 310015, China; Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, China.
  • 2 Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, China.
  • 3 Department of Pharmacy, Shaoxing TCM Hospital Affiliated to Zhejiang Chinese Medical University, Shaoxing 312000, China.
  • 4 School of Medicine, Zhejiang University City College, Hangzhou 310015, China.
  • 5 Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, China.
  • 6 Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou 310014, China. Electronic address: [email protected].
  • 7 Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, China. Electronic address: [email protected].
  • 8 School of Medicine, Zhejiang University City College, Hangzhou 310015, China. Electronic address: [email protected].
PMID: 37011522 DOI: 10.1016/j.bioorg.2023.106494
Abstract

To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFRL858R/T790M with an IC50 value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC50 value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of Apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.

Keywords

Dihydroquinoxalinone; EGFR inhibitors; L858R/T790M; NSCLC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15772
    99.96%, Mutant-Selective EGFR Inhibitor