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

The Phosphodiesterase 3A–Schlafen family member 12 (PDE3A–SLFN12) protein–protein interface is a therapeutic target for a specific class of small-molecule "molecular glues" (de Waal et al., 2016, Nature). These compounds bind to the catalytic domain of PDE3A and induce its association with SLFN12, a protein with latent ribonuclease activity (Garvie et al., 2021, Science). The formation of this ternary complex stabilizes SLFN12 and triggers its RNase function, which specifically targets and cleaves tRNA-Leu-TAA (Wu et al., 2023, Nature Communications). This cleavage leads to ribosome stalling, inhibition of protein synthesis, and the rapid induction of apoptosis in susceptible cells. This mechanism is distinct from traditional PDE3A inhibition, as the cytotoxic effect depends entirely on the recruitment of SLFN12 rather than the modulation of cyclic nucleotide levels. High co-expression of PDE3A and SLFN12 serves as a critical biomarker for sensitivity to these agents, particularly in various cancer types. Clinical drugs such as anagrelide, originally developed for essential thrombocythemia, have been rediscovered to act through this molecular glue mechanism. Targeting this interface offers a precision medicine approach for treating tumors that naturally overexpress both components of the complex.

Other names

PDE3A-SLFN12 complexPDE3A-SLFN12 molecular glue targetPDE3A-SLFN12 interaction

Molecular glue compounds bind to the catalytic pocket of PDE3A, creating a neo-surface that recruits SLFN12. This interaction activates the latent RNase activity of SLFN12, leading to the specific cleavage of tRNA-Leu-TAA, which causes ribosome stalling and triggers apoptosis (Garvie et al., 2021, Science; Wu et al., 2023, Nature Communications).