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

Shilpa Singh, Catherine E. Gleason, Min Fang, Yasmin N. Laimon, Vishal Khivansara, Shanhai Xie, Yavuz T. Durmaz, Aniruddha Sarkar, Kenneth Ngo, Varunika Savla, Yixiang Li, Muhannad Abu-Remaileh, Xinyue Li, Marie-Anais Locquet, Bishma Tuladhar, Ranya Odeh, Frances Hamkins-Indik, Daphne He, Miles W. Membreno, Meisam Nosrati, Nathan N. Gushwa, Siegfried S. F. Leung, Breena Fraga-Walton, Luis Hernandez, Miguel P. Baldomero, Bryan M. Lent, David Spellmeyer, Joshua F. Luna, Dalena Hoang, Yuliana Gritsenko, Manesh Chand, Megan K. DeMart, Sammy Metobo, Chinmay Bhatt, Justin A. Shapiro, Kai Yang, Nathan J. Dupper, Andrew T. Bockus, Jinshu Fang, Ramesh Bambal, Peadar Cremin, John G. Doench, James B. Aggen, Li-Fen Liu, Bernard Levin, Evelyn W. Wang, Iolanda Vendrell, Roman Fischer, Benedikt Kessler, Prafulla C. Gokhale, Sabina Signoretti, Alexander Spektor, Constantine Kreatsoulas, Marie Evangelista, Rajinder Singh, David J. Earp, Deepak Nijhawan, Pablo D. Garcia and Matthew G. Oser ()
Additional contact information
Shilpa Singh: Harvard Medical School
Catherine E. Gleason: Circle Pharma
Min Fang: University of Texas Southwestern Medical Center
Yasmin N. Laimon: Harvard Medical School
Vishal Khivansara: University of Texas Southwestern Medical Center
Shanhai Xie: University of Texas Southwestern Medical Center
Yavuz T. Durmaz: Harvard Medical School
Aniruddha Sarkar: Harvard Medical School
Kenneth Ngo: Harvard Medical School
Varunika Savla: Harvard Medical School
Yixiang Li: Harvard Medical School
Muhannad Abu-Remaileh: Harvard Medical School
Xinyue Li: Harvard Medical School
Marie-Anais Locquet: Harvard Medical School
Bishma Tuladhar: Dana-Farber Cancer Institute
Ranya Odeh: Circle Pharma
Frances Hamkins-Indik: Circle Pharma
Daphne He: Circle Pharma
Miles W. Membreno: Circle Pharma
Meisam Nosrati: Circle Pharma
Nathan N. Gushwa: Circle Pharma
Siegfried S. F. Leung: Circle Pharma
Breena Fraga-Walton: Circle Pharma
Luis Hernandez: Circle Pharma
Miguel P. Baldomero: Circle Pharma
Bryan M. Lent: Circle Pharma
David Spellmeyer: Circle Pharma
Joshua F. Luna: Circle Pharma
Dalena Hoang: Circle Pharma
Yuliana Gritsenko: Circle Pharma
Manesh Chand: Circle Pharma
Megan K. DeMart: Circle Pharma
Sammy Metobo: Circle Pharma
Chinmay Bhatt: Circle Pharma
Justin A. Shapiro: Circle Pharma
Kai Yang: Circle Pharma
Nathan J. Dupper: Circle Pharma
Andrew T. Bockus: Circle Pharma
Jinshu Fang: Circle Pharma
Ramesh Bambal: Circle Pharma
Peadar Cremin: Circle Pharma
John G. Doench: Broad Institute of MIT and Harvard
James B. Aggen: Circle Pharma
Li-Fen Liu: Circle Pharma
Bernard Levin: Circle Pharma
Evelyn W. Wang: Circle Pharma
Iolanda Vendrell: University of Oxford
Roman Fischer: University of Oxford
Benedikt Kessler: University of Oxford
Prafulla C. Gokhale: Harvard Medical School
Sabina Signoretti: Harvard Medical School
Alexander Spektor: Harvard Medical School
Constantine Kreatsoulas: Circle Pharma
Marie Evangelista: Circle Pharma
Rajinder Singh: Circle Pharma
David J. Earp: Circle Pharma
Deepak Nijhawan: University of Texas Southwestern Medical Center
Pablo D. Garcia: Circle Pharma
Matthew G. Oser: Harvard Medical School

Nature, 2025, vol. 646, issue 8085, 734-745

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09433-w

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