Orally Bioavailable Cyclin A/B RxL Inhibitors: Optimization of a Novel Class of Macrocyclic Peptides That Target
Justin A Shapiro1, Nathan J Dupper1, Breena Fraga-Walton1
1Circle 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.
Insights
Researchers developed orally available macrocyclic peptides targeting Cyclin A/B to treat small-cell lung cancer (SCLC). These compounds selectively kill cancer cells and have shown tumor regression in preclinical models, with a lead candidate now in Phase 1 clinical trials.
Area of Science:
- Molecular Biology
- Oncology
- Medicinal Chemistry
Background:
- Cyclins A and B regulate cell cycle progression by activating cyclin-dependent kinases (CDKs).
- Cyclin-Hydrophobic Patch (HP) interactions, involving RxL motifs, are crucial for recruiting substrates and regulators.
- Targeting Cyclin A/B offers a potential therapeutic strategy for cancers with high E2F activity.
Purpose of the Study:
- To optimize macrocyclic peptides that inhibit Cyclin A/B for improved drug-like properties and oral bioavailability.
- To discover a lead compound for oral administration in small-cell lung cancer (SCLC) models.
- To advance Cyclin A/B inhibitors into clinical evaluation.
Main Methods:
- Design and synthesis of macrocyclic peptides targeting the Cyclin A/B Hydrophobic Patch (HP).
- Optimization of lead compounds for oral bioavailability and drug-like properties.
- Evaluation of tumor regression in cell-derived xenograft (CDX) models of SCLC following oral dosing.
Main Results:
- Identification of passively permeable macrocyclic peptides binding to Cyclin A and B HP.
- Demonstration of selective cancer cell killing in cells with high E2F activity.
- Discovery of an optimized lead compound showing tumor regression in SCLC CDX models via oral administration.
- Successful advancement of Cyclin A/B inhibition into a Phase 1 clinical trial.
Conclusions:
- Optimized macrocyclic peptides targeting Cyclin A/B exhibit promising anti-cancer activity and oral bioavailability.
- The lead compound demonstrates efficacy in preclinical SCLC models, supporting its clinical potential.
- Cyclin A/B inhibition represents a viable therapeutic approach for SCLC, currently under clinical investigation.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:39Positive Regulator Molecules
01:45Positive Regulator Molecules
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...