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

The Phosphodiesterase 3A–Schlafen family member 12 (PDE3A–SLFN12) ternary complex is a therapeutic target formed through the action of specific small-molecule molecular glues [1][2]. PDE3A is a phosphodiesterase that typically regulates cyclic nucleotide levels, while SLFN12 is a member of the Schlafen protein family possessing latent ribonuclease (RNase) activity [2][3]. When a molecular glue, such as anagrelide or DNMDP, binds to the catalytic domain of PDE3A, it creates a new molecular interface that recruits SLFN12 [1][4]. This recruitment triggers a conformational change in SLFN12, activating its RNase domain to cleave specific tRNAs, such as tRNA-Leu-TAA, which subsequently inhibits protein translation and induces apoptosis [2][5]. This mechanism is highly specific to cancer cells that co-express both PDE3A and SLFN12, making the complex a promising target for precision oncology [1][6]. The discovery of this complex has redefined the understanding of certain PDE3 inhibitors, shifting their perceived role from simple enzyme inhibitors to facilitators of targeted protein-protein interactions [1][4]. Citations: [1] de Waal, L., et al. (2016) Nat Chem Biol; [2] Garvie, C. W., et al. (2021) Nat Commun; [3] Wu, Y., et al. (2023) Nat Struct Mol Biol; [4] Zimmer, A. D., et al. (2016) Nat Commun; [5] Li, H., et al. (2021) Mol Cell; [6] Katsuda, H., et al. (2022) Cancer Sci.

Other names

PDE3A-SLFN12 complexPDE3A-SLFN12 molecular glue targetPhosphodiesterase 3A-Schlafen 12 complex

Molecular glue-induced ternary complex formation leading to SLFN12-mediated RNase activation and apoptosis.