Computer-aided screening for suppressor of variegation 4-20 homolog 1 inhibitors and their preliminary activity validation in human osteosarcoma

Abstract

Histone methylation/demethylation facilitate to maintain balanced histone methylation levels and underpin gene regulation, playing the key roles in epigenetic regulation. Suppressor of variegation 4-20 homolog 1 (SUV420H1), a member of class Histone Lysine Methyltransferase and a key enzyme in the epigenetic regulation of the pathways controlling metabolism and tumorigenesis, is crucial to maintain cell homeostasis. The inhibition of SUV420H1 has emerged as a promising candidate for drug development and cancer therapy. Herein, two potential and potent SUV420H1 inhibitors (ZINC08398384, ZINC08439608) were identified through in silico approach and in vitro biological experiments. In vitro biological tests demonstrated that these compounds can inhibit the proliferation of U2OS cells and restrict its migration ability. And the level of dimethylation of lysine 20 on histone H4 (H4K20me2) was markedly decreased by these compounds-treatment in a dose-dependent manner. These results indicated that ZINC08398384 and ZINC08439608 are potential SUV420H1 inhibitors and could be developed as promising drug candidates applied to cancer epigenetic therapy.

Communicated by Ramaswamy H. Sarma

Keywords:

• SUV420H1
• histone lysine methyltransferases
• H4K20me2
• molecular docking
• molecular dynamics simulation
• virtual screening

Acknowledgements

The authors are grateful for all support provided by Sichuan University. And Li Jianzong, Li Yuanyuan, Lu Kaimin and Zhao Liming for their valuable suggestions.

Disclosure statement

The authors declare that they have no competing interests.

Author contribution

The contributions of each author to the contents of this manuscript are as follows. Study design: JB, CW; experiments operation: RZ, DL, NJ, XL; data collection and analysis: RZ, DL, XW, JZ, MW; manuscript write: RZ, XL, NJ.

Data availability statement

Availability of data and material: All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Additional information

Funding

This work was supported in part by National Natural Science Foundation of China (No. 81373311), Key Project of Research and Development of Sichuan under Grant (2018SZ0026).