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, , an improved compound, , was discovered to be potent in cells and active in several tumor models . More analogs were prepared and tested with the goal of increasing metabolic stability and decreasing PDE3 inhibition while maintaining the cellular activity of .

Velcrin molecular glues induce apoptosis in glioblastomas with high and expression.

Background: Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase SLFN12 and the phosphodiesterase PDE3A. Formation of the complex activates SLFN12, which cleaves tRNA(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the cancer cell line encyclopedia, including glioblastoma cell lines.

Velcrin compounds activate the SLFN12 tRNase to induce tomoptosis.

Velcrins are molecular glues that induce complex formation between PDE3A and SLFN12. The PDE3A-SLFN12 complex activates the SLFN12 RNase, resulting in cleavage of the specific substrate, tRNA-Leu-TAA, global inhibition of translation, and death of cells expressing sufficient levels of both proteins. Here, unanswered questions about the mechanism of action and therapeutic promise of velcrin compounds are discussed.