Cyclin A and B hydrophobic patch (HP)

The Cyclin A/B RxL interaction target refers to the protein-protein interaction interface located on the conserved hydrophobic patch of Cyclin A and Cyclin B [1, 8]. This site facilitates the recruitment of substrates and regulatory proteins containing a short linear motif known as the RxL motif or Cy-motif, such as E2F transcription factors and the kinase Myt1 [2, 11]. In normal cells, these interactions are essential for the timed phosphorylation of proteins that drive DNA replication and mitotic entry [3, 11]. However, in cancers characterized by the loss of tumor suppressors like RB1 and TP53, the cell cycle is dysregulated, making these cells uniquely vulnerable to further perturbation of E2F activity [7, 12, 14]. Therapeutic macrocyclic inhibitors, such as CID-078, target this interface to competitively block RxL-mediated binding [4, 7, 8].\n\nThis inhibition results in the hyperactivation of E2F1, leading to catastrophic replication stress and DNA damage [1, 4]. Simultaneously, the disruption of the Cyclin B-Myt1 interaction removes an inhibitory brake, causing premature activation of the Cyclin B-CDK1 complex [2, 5, 9]. Together, these effects force damaged cancer cells into an aborted mitosis, triggering the spindle assembly checkpoint and inducing apoptosis [1, 3, 7]. This approach is currently being evaluated in clinical trials for small cell lung cancer and other E2F-high malignancies [4, 7, 14].

Other names

Cyclin A/B RxL interactionCyclin A/B RxL recruitment siteRxL-motif binding siteCy-motif interaction siteCyclin recruitment siteMRAIL motif siteHydrophobic patch

Competitive inhibition of RxL-motif binding to the hydrophobic patch of Cyclins A and B, which disrupts substrate recruitment and regulatory feedback loops, leading to E2F1 hyperactivation and premature mitotic entry [1, 4, 8].