Discovery of Cell-Permeable Macrocyclic Cyclin A/B RxL Inhibitors that Demonstrate Antitumor Activity

The cyclin-dependent kinase (CDK)/retinoblastoma protein
(RB)/early
region 2 binding factor (E2F) axis forms the core transcriptional
machinery driving cell cycle progression. Alterations in RB1 or other pathway members occur in many cancers, resulting in heightened
oncogenic E2F activity. The activity of E2F is regulated by RxL-mediated
binding to the hydrophobic patch (HP) of Cyclin A; blocking this interaction
results in the hyperactivation of E2F and synthetic lethality in E2F-driven
tumors. While mechanistically differentiated and potentially more
selective than blocking CDK activity (e.g., CDK2 or CDK4 inhibitors),
the Cyclin A/E2F RxL interaction was deemed undruggable. Utilizing
structure-based design, we have discovered a family of cell-permeable
macrocyclic Cyclin A/B RxL inhibitors that show potent and selective
activity against RB1/E2F-dysregulated
cancer cell lines. Lead compound 34 demonstrated proof-of-concept
efficacy via intraperiotoneal (IP) administration in mouse cell line-derived
xenograft (CDX) tumor models.