Discovery of Cell-Permeable Macrocyclic Cyclin A/B RxL Inhibitors that Demonstrate Antitumor Activity
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 <i>RB1</i> 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 <i>RB1</i>/<i>E2F</i>-dysregulated cancer cell lines. Lead compound <b>34</b> demonstrated proof-of-concept efficacy via intraperiotoneal (IP) administration in mouse cell line-derived xenograft (CDX) tumor models.
Authors
- Ramesh Bambal (ORCID: https://orcid.org/0000-0002-4313-3888)
- Daphne He
- Marie Evangelista (ORCID: https://orcid.org/0000-0003-4623-1595)
- Peadar Cremin
- Evelyn W. Wang
- Siegfried S. F. Leung
- Catherine E. Gleason
- Frances Hamkins-Indik
- Nathan J. Dupper
- Jinshu Fang
- Cayla M. McEwen
- Pablo D. García
- Megan K. DeMart
- Ranya Odeh
- David C. Spellmeyer (ORCID: https://orcid.org/0009-0002-9259-0767)
- David J. Earp
- Mahesh Ramaseshan
- Andrew T. Bockus (ORCID: https://orcid.org/0000-0001-5522-6523)
- James B. Aggen (ORCID: https://orcid.org/0000-0001-7989-5131)
- Luis Ortiz-Hernández (ORCID: https://orcid.org/0000-0002-5870-1729)
- Miles W. Membreño
- Constantine Kreatsoulas (ORCID: https://orcid.org/0000-0002-3654-8209)
- Justin A. Shapiro (ORCID: https://orcid.org/0000-0001-9891-0464)
- Rajinder Singh (ORCID: https://orcid.org/0000-0001-7991-5083)
- Jie Zheng (ORCID: https://orcid.org/0000-0001-5241-3630)
- Breena Fraga-Walton
- Miguel P. Baldomero
- Joshua F. Luna
- Bernard Levin
- Dalena Hoang
- Manesh Chand
- Bryan M. Lent
- Yuliana Gritsenko
- Meisam Nosrati
Institutions
- Sunesis (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-14
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00253
- Citations
- 5
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 4.03