Targeting a Cyclin D1 folding intermediate to clear the protein as it forms
- Unreviewed preprint: simulations of how Cyclin D1 folds revealed a short-lived intermediate that small molecules can bind.
- Structure-guided compounds engaging that state selectively trigger loss of newly made Cyclin D1 protein.
- In cells and animals, the approach dampened Cyclin D1 signaling, slowed tumor growth, and stayed active in a CDK4/6 inhibitor-resistant model.
💡 Points
Going after a transient folding intermediate instead of the native fold is a clever way around Cyclin D1's lack of a classic pocket, and it yields a degrader-like outcome by a different route. My worry is selectivity: other cyclins may share intermediate features, and a short-lived state is hard to confirm by SAR. Activity in CDK4/6i-resistant models is the interesting bit; I'd want compound structures and potency first.
Protein Folding Interference Enables Selective Cyclin D1 Degradation ↗