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.
Subject(s)
Antineoplastic Agents , Apoptosis , Cell Proliferation , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase 6 , Drug Design , Humans , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Cyclin-Dependent Kinase 6/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Apoptosis/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Jurkat Cells , Structure-Activity Relationship , Proteolysis/drug effects , Molecular StructureABSTRACT
The recent COVID-19 crisis caught many by surprise. Yet some firms were better prepared to weather the downturn than others. Using a comprehensive data set that observes over 15,000 firms in 27 countries, including several developing countries, shortly before and after the pandemic, we document that pre-crisis innovation affected firm's survival odds and performance thereafter. The results show that innovative firms are less likely to close and perform better than non-innovators during the pandemic crisis. Innovative firms are also more optimistic about the future than non-innovators. Our results further indicate that firm's adaptability mediates the relationship between innovation and survival outcomes. The study finding shows that innovative firms are more likely to introduce new products, remote work arrangements, increase delivery, pivoting, and online activities than non-innovators during the pandemic crisis.