1. Development of CDK2 and CDK5 Dual Degrader TMX-2172.
- Author
-
Teng M, Jiang J, He Z, Kwiatkowski NP, Donovan KA, Mills CE, Victor C, Hatcher JM, Fischer ES, Sorger PK, Zhang T, and Gray NS
- Subjects
- Cell Division drug effects, Cell Line, Tumor, Cyclin-Dependent Kinase 2 metabolism, Cyclin-Dependent Kinase 5 metabolism, Drug Screening Assays, Antitumor, Female, Humans, Ovarian Neoplasms enzymology, Ovarian Neoplasms pathology, Phosphorylation, Cyclin-Dependent Kinase 2 antagonists & inhibitors, Cyclin-Dependent Kinase 5 antagonists & inhibitors, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors pharmacology
- Abstract
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., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2020
- Full Text
- View/download PDF