2. Academic Validation
  3. Development of CDK2 and CDK5 Dual Degrader TMX-2172

Development of CDK2 and CDK5 Dual Degrader TMX-2172

  • Angew Chem Int Ed Engl. 2020 Aug 10;59(33):13865-13870. doi: 10.1002/anie.202004087.
Mingxing Teng 1 2,  Jie Jiang 1 2,  Zhixiang He 1 2,  Nicholas P Kwiatkowski 1 2,  Katherine A Donovan 1 2,  Caitlin E Mills 3,  Chiara Victor 3,  John M Hatcher 1 2,  Eric S Fischer 1 2,  Peter K Sorger 3,  Tinghu Zhang 1 2,  Nathanael S Gray 1 2
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
PMID: 32415712 DOI: 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

CDK2; CDK5; cancer; cell cycle; drug design; protein degradation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-151071
    CDKs抑制剂
    CDK
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