Discovery of BAY 2666605, a Molecular Glue for PDE3A and SLFN12
A subset of phosphodiesterase 3 (PDE3) inhibitors kills cancer cells that express both PDE3A and SLFN12 by inducing a protein-protein interaction between the two, triggering SLFN12 tRNase activity. Following discovery of the prototypical tool compound, <b>DNMDP</b>, an improved compound, <b>BRD9500</b>, was discovered to be potent in cells and active in several tumor models <i>in vivo</i>. More analogs were prepared and tested with the goal of increasing metabolic stability and decreasing PDE3 inhibition while maintaining the cellular activity of <b>BRD9500</b>. This led to the discovery of <b>BAY 2666605</b>, a compound optimized for clinical testing.
Authors
- Luc de Waal
- Stefan Gradl
- Silvia Goldoni
- Heidi Greulich (ORCID: https://orcid.org/0000-0001-5571-9862)
- Timothy A. Lewis (ORCID: https://orcid.org/0000-0001-9748-9575)
- Manuel Ellermann
- Xiaoyun Wu (ORCID: https://orcid.org/0000-0001-6735-8099)
- Matthew Meyerson (ORCID: https://orcid.org/0000-0002-9133-8108)
- Martin Lange (ORCID: https://orcid.org/0000-0002-4045-3915)
- Charlotte Kopitz
- Philip Lienau (ORCID: https://orcid.org/0000-0002-6048-4559)
- Adrian Tersteegen
- Stefan Kaulfuß
- Karsten Denner
Institutions
- Broad Institute (US)
- Bayer (United States) (US)
- Dana-Farber Cancer Institute (US)
- Bayer (Germany) (DE)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-09-10
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00336
- Citations
- 6
- Primary Topic
- Phosphodiesterase function and regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Bayer
- Broad Institute
- Pharmaceuticals Bayer