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 PMID: 41721763

ADC Targets in Oncology

2026-04-10

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

J Med Chem. 2026 Mar 12;69(5):5441-5460. doi: 10.1021/acs.jmedchem.5c02445.

Justin A Shapiro ¹ , Nathan J Dupper ¹ , Breena Fraga-Walton ¹ , Andrew T Bockus ¹ , Siegfried S F Leung ¹ , Kai Yang ¹ , Chinmay Bhatt ¹ , Megan K DeMart ¹ , Miguel P Baldomero ¹ , Luis Hernandez ¹ , Gabriel Fung ¹ , Sammy Metobo ¹ , Steven Xie ¹ , Bryan M Lent ¹ , David C Spellmeyer ¹ , Joshua Luna ¹ , Dalena Hoang ¹ , Manesh Chand ¹ , Yuliana Gritsenko ¹ , Catherine E Gleason ¹ , Frances Hamkins-Indik ¹ , Jie Zheng ¹ , Ranya Odeh ¹ , Meisam Nosrati ¹ , Daphne He ¹ , Ramesh Bambal ¹ , Peadar Cremin ¹ , Jinshu Fang ¹ , Bernard Levin ¹ , Evelyn W Wang ¹ , Marie Evangelista ¹ , David Earp ¹ , Constantine Kreatsoulas ¹ , Rajinder Singh ¹ , Pablo D Garcia ¹ , James B Aggen ¹

Affiliations

Abstract

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.