Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors
- Nature. 2025 Aug 20. doi: 10.1038/s41586-025-09433-w.
- 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- 2. Circle Pharma, San Francisco, CA, USA.
- 3. Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- 4. Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
- 5. Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.
- 6. Belfer Center for Applied Cancer Science, Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA, USA.
- 7. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
- 8. Target Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
- 9. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
- 10. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
- 11. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
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 activity1. 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 activity2,3. Although E2F activation is essential for cell cycle progression, hyperactivation promotes Apoptosis4-9, presenting a therapeutic vulnerability. Cyclin proteins use a conserved hydrophobic patch to bind to substrates bearing short linear RxL motifs10-13. Cyclin A represses E2F through an RxL-dependent interaction10,14, which, when disrupted, hyperactivates E2F15. 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.
-
Cat. No.Product NameDescriptionTargetResearch Area
-
-