Development of CDK2 and CDK5 Dual Degrader TMX‐2172
- 3 June 2020
- journal article
- research article
- Published by Wiley in Angewandte Chemie-International Edition
- Vol. 59 (33), 13865-13870
- https://doi.org/10.1002/anie.202004087
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.Keywords
Funding Information
- National Institutes of Health (R01CA218278, P01CA154303)
This publication has 44 references indexed in Scilit:
- Cyclin-dependent kinase inhibitors move into Phase IIINature Reviews Drug Discovery, 2012
- Mammalian Interphase Cdks: Dispensable Master Regulators of the Cell CycleGenes & Cancer, 2012
- Cdk5: a multifaceted kinase in neurodegenerative diseasesTrends in Cell Biology, 2012
- Discovery of a Potential Allosteric Ligand Binding Site in CDK2ACS Chemical Biology, 2011
- Cyclin-dependent kinases and cell-cycle transitions: does one fit all?Nature Reviews Molecular Cell Biology, 2008
- CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repairNature, 2005
- Identification of Interaction Partners and Substrates of the Cyclin A1-CDK2 ComplexPublished by Elsevier BV ,2004
- A decade of CDK5Nature Reviews Molecular Cell Biology, 2001
- Developmental Control of Cell Cycle Regulators: A Fly's PerspectiveScience, 1996
- Increased and altered DNA binding of human p53 by S and G2/M but not Gl cyclin-dependent kinasesNature, 1995