Development of CDK2 and CDK5 Dual Degrader TMX‐2172
Autor: | Nathanael S. Gray, Tinghu Zhang, Caitlin E. Mills, John M. Hatcher, Peter K. Sorger, Eric S. Fischer, Nicholas Kwiatkowski, Jie Jiang, Chiara Victor, Mingxing Teng, Katherine A. Donovan, Zhixiang He |
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Rok vydání: | 2020 |
Předmět: |
Protein degradation
010402 general chemistry 01 natural sciences Article Catalysis Cyclin-dependent kinase Cell Line Tumor Humans Phosphorylation Protein Kinase Inhibitors Ovarian Neoplasms Cyclin-dependent kinase 1 biology 010405 organic chemistry Chemistry Cyclin-Dependent Kinase 2 Cyclin-dependent kinase 2 Cyclin-Dependent Kinase 5 General Medicine General Chemistry Cell cycle 0104 chemical sciences Cancer research biology.protein Female Cyclin-dependent kinase 9 Cyclin-dependent kinase 6 Drug Screening Assays Antitumor biological phenomena cell phenomena and immunity Cyclin-dependent kinase 7 Cell Division |
Zdroj: | Angew Chem Int Ed Engl |
ISSN: | 1521-3773 1433-7851 |
Popis: | Cyclin-dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of cancer. Development of CDK2 inhibitors has been extremely challenging as its ATP-binding site shares high similarity with CDK1, a related kinase whose inhibition causes toxic effects. Here, we report the development of TMX-2172, a heterobifunctional CDK2 degrader with degradation selectivity for CDK2 and CDK5 over not only CDK1, but transcriptional CDKs (CDK7 and CDK9) and cell cycle CDKs (CDK4 and CDK6) as well. In addition, we demonstrate that antiproliferative activity in ovarian cancer cells (OVCAR8) depends on CDK2 degradation and correlates with high expression of cyclin E1 (CCNE1), which functions as a regulatory subunit of CDK2. Collectively, our work provides evidence that TMX-2172 represents a lead for further development and that CDK2 degradation is a potentially valuable therapeutic strategy in ovarian and other cancers that overexpress CCNE1. |
Databáze: | OpenAIRE |
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