Design, Synthesis, and Activity Assays of Cyclin-Dependent Kinase 1 Inhibitors With Flavone Scaffolds

Lanlan Fu; Jiajia Mou; Yanru Deng; Xiaoliang Ren; Shuang Qiu

doi:10.3389/fchem.2022.940427

Design, Synthesis, and Activity Assays of Cyclin-Dependent Kinase 1 Inhibitors With Flavone Scaffolds

Front Chem. 2022 Aug 8:10:940427. doi: 10.3389/fchem.2022.940427. eCollection 2022.

Authors

Lanlan Fu¹, Jiajia Mou¹, Yanru Deng¹, Xiaoliang Ren¹, Shuang Qiu¹

Affiliation

¹ School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China.

Abstract

Cyclin-dependent kinase 1 (CDK1) plays an indispensable role in the whole cell cycle. It has become a new target for cancer therapy. According to the binding mode of a pan-CDK inhibitor, flavopiridol with CDK1, and our previous work, a new series of flavone derivatives were discovered. Among them, compound 2a showed the best CDK1 inhibitory and anti-proliferative potencies in the in vitro activity investigation. The IC₅₀ of 2a against CDK1 was 36.42 ± 1.12 μM vs. 11.49 μM ± 0.56 of flavopiridol. In the anti-proliferation activity assays, 2a exhibited better activity toward RAW264.7 than MCF-7 cells. The results indicated that flavone derivatives, besides inhibiting the growth of tumor cells, can also antagonize inflammatory response. Molecular docking results showed that conformation of 2a can form hydrogen bonds and various hydrophobic interactions with the key amino acid residues of CDK1. It can be used as a promising lead compound for CDK1 inhibitor development.

Keywords: anti-tumor; cyclin-dependent kinase 1; derivative; flavone; inhibitor.