Phosphodiesterase 3A–Schlafen family member 12 protein complex (PDE3A–SLFN12) (PDE3A–SLFN12)

The Phosphodiesterase 3A–Schlafen family member 12 (PDE3A–SLFN12) protein complex is a gain-of-function molecular assembly that serves as a target for a specific class of antineoplastic small molecules known as molecular glues (de Waal et al., 2016, Nature). Under normal physiological conditions, PDE3A regulates intracellular signaling by hydrolyzing cAMP and cGMP, while SLFN12 remains an inactive endoribonuclease (Garvie et al., 2021, Nature Communications). When a molecular glue such as DNMDP or anagrelide binds to the catalytic site of PDE3A, it alters the protein's surface to promote a high-affinity interaction with SLFN12. This recruitment activates SLFN12's RNase activity, leading to the site-specific cleavage of tRNA-Leu-TAA, which halts protein translation and triggers apoptosis (Nombela et al., 2022, Nature Reviews Cancer). Because this cytotoxic effect is strictly dependent on the presence of both proteins, the complex represents a precision medicine target for cancers that co-express PDE3A and SLFN12.

Other names

PDE3A-SLFN12 complexPDE3A/SLFN12 complexPhosphodiesterase 3A-Schlafen 12 complex

Molecular glue-induced stabilization of the PDE3A-SLFN12 complex, which activates the latent ribonuclease activity of SLFN12, leading to tRNA-Leu-TAA degradation, inhibition of protein synthesis, and induction of apoptosis (de Waal et al., 2016, Nature; Garvie et al., 2021, Nature Communications).