# 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

## TL;DR

Researchers developed orally available drugs that target cyclin A/B to treat cancers with high E2F activity and compromised cell cycle checkpoints.

## Contribution

Optimized macrocyclic peptides with oral bioavailability that inhibit cyclin A/B and show tumor regression in preclinical models.

## Key findings

- Macrocyclic peptides targeting cyclin A/B's hydrophobic patch selectively kill E2F-high cancer cells.
- Lead compound achieved tumor regression in SCLC models via oral administration.
- Phase 1 clinical trial is ongoing to evaluate cyclin A/B inhibition in humans.

## 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.