1. Academic Validation
  2. Targeting G1-S-checkpoint-compromised cancers with cyclin A/B RxL inhibitors

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

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. matthew_oser@dfci.harvard.edu.
  • 11 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. matthew_oser@dfci.harvard.edu.
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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