Discovery of Cell-Permeable Macrocyclic Cyclin A/B RxL Inhibitors that Demonstrate Antitumor Activity
Year: 2025
Type: article
Abstract: The cyclin-dependent kinase (CDK)/retinoblastoma protein (RB)/early region 2 binding factor (E2F) axis forms the core transcriptional machinery driving cell cycle progression. Alterations in RB1 or other pathway members occur in many cancers, resulting in heightened oncogenic E2F activity. The activity of E2F is regulated by RxL-mediated binding to the hydrophobic patch (HP) of Cyclin A; blocking this interaction results in the hyperactivation of E2F and synthetic lethality in E2F-driven tumors. While mechanistically differentiated and potentially more selective than blocking CDK activity (e.g., CDK2 or CDK4 inhibitors), the Cyclin A/E2F RxL interaction was deemed undruggable. Utilizing structure-based design, we have discovered a family of cell-permeable macrocyclic Cyclin A/B RxL inhibitors that show potent and selective activity against RB1/E2F-dysregulated cancer cell lines. Lead compound 34 demonstrated proof-of-concept efficacy via intraperiotoneal (IP) administration in mouse cell line-derived xenograft (CDX) tumor models.
Source: Journal of Medicinal Chemistry
Authors: Andrew T. Bockus, Siegfried S. F. Leung, Breena Fraga-Walton, Miguel P. Baldomero, Luis Hernandez, Nathan J. Dupper, Justin A. Shapiro, Bryan M. Lent, David C. Spellmeyer, Megan K. DeMart, Joshua Luna, Dalena Hoang, Manesh Chand, Yuliana Gritsenko, Cayla McEwen, Mahesh Ramaseshan, Catherine E. Gleason, Frances Hamkins-Indik, Miles W. Membreno, Jie Zheng, Ranya Odeh, Meisam Nosrati, Daphne He, Ramesh Bambal, Peadar Cremin, Jinshu Fang, Bernard Levin, Evelyn W. Wang, Marie Evangelista, David Earp, Constantine Kreatsoulas, Rajinder Singh, Pablo D. Garcia, James B. Aggen
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4413138975