Orally Bioavailable Cyclin A/B RxL Inhibitors: Optimization of a Novel Class of Macrocyclic Peptides That Target E2F-High and G1–S-Checkpoint-Compromised Cancers
Year: 2026
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide Cyclins A and B bind and activate their cognate cyclin-dependent kinase (CDK) to regulate progression through the S and G2/M phases of the cell cycle, respectively. Cyclins recruit substrates and regulators through the binding of an RxL motif with a Hydrophobic Patch (HP) on the cyclin surface. We recently disclosed the first class of passively permeable macrocyclic peptides that bind to the HP of both Cyclin A and Cyclin B and selectively kill cancer cells with high E2F activity. We used a lead example to demonstrate in vivo tumor regression in cell-line-derived xenograft models of small-cell lung cancer (SCLC) via intraperitoneal dosing. Here we describe the optimization of this series for drug-like properties and oral bioavailability, resulting in the discovery of a lead compound, which demonstrates tumor regression in CDX models of SCLC via oral dosing. We are currently evaluating Cyclin A/B inhibition in a Phase 1 clinical trial.
Source: Journal of Medicinal Chemistry
Authors: Justin A. Shapiro, Nathan J. Dupper, Breena Fraga-Walton, Andrew T. Bockus, Siegfried S.F. Leung, Kai Yang, Chinmay Bhatt, Megan K. DeMart, Miguel P. Baldomero, Luis Hernandez, Gabriel Fung, Sammy Metobo, Steven Xie, Bryan M. Lent, David C. Spellmeyer, Joshua Luna, Dalena Hoang, Manesh Chand, Yuliana Gritsenko, Catherine E. Gleason, Frances Hamkins-Indik, 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: W7130835037