Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors

  • Nature. 2025 Aug 20. doi: 10.1038/s41586-025-09433-w.
Shilpa Singh  1 Catherine E Gleason  2 Min Fang  3 Yasmin N Laimon  4 Vishal Khivansara  3 Shanhai Xie  3 Yavuz T Durmaz  1 Aniruddha Sarkar  5 Kenneth Ngo  1  6 Varunika Savla  4 Yixiang Li  1 Muhannad Abu-Remaileh  1 Xinyue Li  1 Marie-Anais Locquet  1 Bishma Tuladhar  6 Ranya Odeh  2 Frances Hamkins-Indik  2 Daphne He  2 Miles W Membreno  2 Meisam Nosrati  2 Nathan N Gushwa  2 Siegfried S F Leung  2 Breena Fraga-Walton  2 Luis Hernandez  2 Miguel P Baldomero  2 Bryan M Lent  2 David Spellmeyer  2 Joshua F Luna  2 Dalena Hoang  2 Yuliana Gritsenko  2 Manesh Chand  2 Megan K DeMart  2 Sammy Metobo  2 Chinmay Bhatt  2 Justin A Shapiro  2 Kai Yang  2 Nathan J Dupper  2 Andrew T Bockus  2 Jinshu Fang  2 Ramesh Bambal  2 Peadar Cremin  2 John G Doench  7 James B Aggen  2 Li-Fen Liu  2 Bernard Levin  2 Evelyn W Wang  2 Iolanda Vendrell  8 Roman Fischer  8 Benedikt Kessler  8 Prafulla C Gokhale  1  6 Sabina Signoretti  4  9 Alexander Spektor  5 Constantine Kreatsoulas  2 Marie Evangelista  2 Rajinder Singh  2 David J Earp  2 Deepak Nijhawan  3 Pablo D Garcia  2 Matthew G Oser  10  11
Affiliations
  • 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].
Abstract

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.

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