2. Academic Validation
  3. 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments as selective dual-targeting inhibitors of HIF-1α and EZH2 for the treatment of lung cancer

2,2- dimethylbenzopyran derivatives containing pyridone structural fragments as selective dual-targeting inhibitors of HIF-1α and EZH2 for the treatment of lung cancer

  • Bioorg Chem. 2024 Jun:147:107419. doi: 10.1016/j.bioorg.2024.107419.
Huashen Xu 1,  Jie Zhang 2,  Junning Zhuang 1,  Yuanguang Chen 1,  Lu Chen 1,  Jianmin Wang 2,  Ruolin Cao 1,  Fuqin Liu 1,  Kaibo Wang 1,  Xiaoyu Zhang 3,  Lihui Wang 4,  Guoliang Chen 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi 117004, PR China.
  • 3 School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
  • 4 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi 117004, PR China. Electronic address: wlhcw@163.com.
  • 5 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: spucgl@163.com.
PMID: 38703440 DOI: 10.1016/j.bioorg.2024.107419
Abstract

We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 Enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α Inhibitor previously reported by our group, and Tazemetostat, an EZH2 Inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds.

Keywords

Anti-tumor; EZH2; HIF-1α; HIF-1α/EZH2 dual-targeting inhibitor; Non-small cell lung cancer.

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