2. Academic Validation
  3. Development of Degraders of Cyclin-Dependent Kinases 4 and 6 Based on Rational Drug Design

Development of Degraders of Cyclin-Dependent Kinases 4 and 6 Based on Rational Drug Design

  • J Med Chem. 2024 Jul 11;67(13):11354-11364. doi: 10.1021/acs.jmedchem.4c00965.
Huan He 1 2,  Xingsen Zhang 2,  Jie Wang 2,  Qi Liu 2,  LeiHao Zhang 2,  Lu Chen 2,  Yuan Yuan 2,  Zhenjiang Zhao 2,  Honglin Li 1 2 3,  Zhuo Chen 2
Affiliations

Affiliations

  • 1 Innovation Center for AI and Drug Discovery (ICAIDD), East China Normal University, Shanghai 200062, China.
  • 2 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 3 Lingang Laboratory, Shanghai 200031, China.
PMID: 38943626 DOI: 10.1021/acs.jmedchem.4c00965
Abstract

Degradation of target proteins has been considered to be a promising therapeutic approach, but the rational design of compounds for degradation remains a challenge. In this study, we reasonably designed and synthesized only 10 compounds to discover effective CDK4/6 protein degraders. Among the newly synthesized compounds, 7f achieved dual degradation of CDK4/6 protein, with DC50 values of 10.5 and 2.5 nM, respectively. Compound 7f also exhibited inhibitory proliferative activity against Jurkat cells with an IC50 value of 0.18 μM. Furthermore, 7f induced cell Apoptosis and G1 phase cell cycle arrest in a dose-dependent manner in Jurkat cells. In conclusion, these findings demonstrate the potential of 7f as a CDK4/6 degrader and a potential therapeutic strategy against Cancer, thereby expanding the potential of CDK4/6 dual PROTACs.

Figures
Products