TY - JOUR
T1 - Development of Degraders of Cyclin-Dependent Kinases 4 and 6 Based on Rational Drug Design
AU - He, Huan
AU - Zhang, Xingsen
AU - Wang, Jie
AU - Liu, Qi
AU - Zhang, Lei Hao
AU - Chen, Lu
AU - Yuan, Yuan
AU - Zhao, Zhenjiang
AU - Li, Honglin
AU - Chen, Zhuo
N1 - Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/7/11
Y1 - 2024/7/11
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85197047007
U2 - 10.1021/acs.jmedchem.4c00965
DO - 10.1021/acs.jmedchem.4c00965
M3 - 文章
C2 - 38943626
AN - SCOPUS:85197047007
SN - 0022-2623
VL - 67
SP - 11354
EP - 11364
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 13
ER -
