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, DNMDP, an improved compound, BRD9500, was discovered to be potent in cells and active in several tumor models in vivo. More analogs were prepared and tested with the goal of increasing metabolic stability and decreasing PDE3 inhibition while maintaining the cellular activity of BRD9500. This led to the discovery of BAY 2666605, a compound optimized for clinical testing.