S-phase kinase-associated protein 2 – Cyclin-dependent kinase inhibitor 1B protein-protein interface (SKP2-p27 PPI)

The S-phase kinase-associated protein 2 (SKP2) – Cyclin-dependent kinase inhibitor 1B (p27) protein-protein interface is a critical regulatory node in the eukaryotic cell cycle (UniProt Q13309, P46527). SKP2 serves as the substrate-recognition component of the SCF^SKP2 E3 ubiquitin ligase complex, which mediates the polyubiquitination and subsequent proteasomal degradation of the tumor suppressor p27 (Wu et al., 2012, Nature). Because p27 acts as a potent inhibitor of cyclin-dependent kinases (CDKs) to prevent premature entry into the S-phase, its degradation is essential for cell cycle progression. In many human cancers, SKP2 is overexpressed, leading to pathologically low levels of p27, which promotes uncontrolled cell proliferation and genomic instability (Chan et al., 2013, Cell). Pharmacological targeting of this specific interface aims to stabilize p27 levels by preventing its recruitment to the SCF complex, thereby restoring cell cycle checkpoints and inducing growth arrest or apoptosis in malignant cells. Small molecule inhibitors like C1, C20, and SZL-P1-41 have demonstrated the feasibility of disrupting this interaction, offering a targeted approach to treat SKP2-overexpressing malignancies (Wu et al., 2012; Chan et al., 2013).

Other names

SKP2-p27Kip1 interfaceSKP2-CDKN1B interactionSCF-SKP2-p27 complexSKP2-CKS1-p27 interface

Small molecule inhibition of the protein-protein interaction between the F-box protein SKP2 and its substrate p27, preventing p27 recruitment to the SCF complex and subsequent ubiquitination (Wu et al., 2012, Nature).