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Small-cell lung cancers (SCLCs) contain near-universal loss-of-function mutations in RB1 and TP53, compromising the G1-S checkpoint and leading to dysregulated E2F activity. Other cancers similarly disrupt the G1-S checkpoint through loss of CDKN2A or amplification of cyclin D or cyclin E, also resulting in excessive E2F activity. Although E2F activation is essential for cell cycle progression, hyperactivation promotes apoptosis, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs. Cyclin A represses E2F through an RxL-dependent interaction, which, when disrupted, hyperactivates E2F. However, this substrate interface has remained difficult to target. Here we developed cell-permeable, orally bioavailable macrocyclic peptides that inhibit RxL-mediated interactions of cyclins with their substrates. Dual inhibitors of cyclin A and cyclin B RxL motifs (cyclin A/Bi) selectively kill SCLC cells and other cancer cells with high E2F activity. Genetic screens revealed that cyclin A/Bi induces apoptosis through cyclin B- and CDK2-dependent spindle assembly checkpoint activation. Mechanistically, cyclin A/Bi hyperactivates E2F and cyclin B by blocking cyclin A-E2F and cyclin B-MYT1 RxL interactions. Notably, cyclin A/Bi promoted the formation of neomorphic cyclin B-CDK2 complexes, which drive spindle assembly checkpoint activation and mitotic cell death. Finally, orally administered cyclin A/Bi showed robust anti-tumour activity in chemotherapy-resistant SCLC patient-derived xenografts. These findings reveal gain-of-function mechanisms through which cyclin A/Bi triggers apoptosis and support their development for E2F-driven cancers.