1. Academic Validation
  2. 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

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

Affiliation

  • 1 Circle Pharma, 169 Harbor Way, South San Francisco, California 94080, United States.
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.

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