Researchers at Dana-Farber, UT Southwestern, and Circle Pharma developed macrocyclic peptide drugs that block cyclin A and cyclin B from binding their substrates via RxL motifs. These dual inhibitors (cyclin A/Bi) selectively kill small-cell lung cancer (SCLC) cells and other cancers with high E2F activity — a feature driven by RB1 or TP53 loss — while largely sparing normal cells. The compounds work by simultaneously hyperactivating E2F transcription and unleashing cyclin B, which together trigger an aberrant spindle assembly checkpoint response and mitotic cell death. Oral dosing showed robust anti-tumor activity in chemotherapy-resistant SCLC patient-derived xenograft models, suggesting a first-in-class therapeutic strategy for one of oncology's most lethal and treatment-resistant cancers.
