Command Palette

Search for a command to run...

Preprint WatchModerateOctober 30th, 2026

Identification and inhibition of the Cyclin D Rb-docking interface that drives cell division

Topacio, B. R.; Fleming, C.; Lanz, M.; Ord, M.; Memarpoor-Yazdi, M.; Zhang, S.; Xie, S.; Tuvikene, J.; Weaver, A.; Sanidas, I.; Davey, N.; Pryciak, P.; Sage, J.; Rubin, S.; Koivomagi, M.; Skotheim, J.

D-type cyclins dock the retinoblastoma protein through an A2 prime helix interface distinct from the p27-occupied hydrophobic patch, and mutating that interface slows proliferation, positioning the docking site as a target separate from the CDK4 and CDK6 ATP pocket.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

A bioRxiv preprint reports that D-type cyclins dock the retinoblastoma protein through an A2 prime helix interface distinct from the hydrophobic patch occupied by p27, and that mutating this interface slows proliferation, positioning the cyclin D to Rb docking site as a drug target separate from the CDK4 and CDK6 ATP pocket. The Claidex graph holds two CDK6 failures, abemaciclib-cdk46-hnscc-window-aim-soc-shift and lerociclib-cdk46-eqrx-shutdown-hr-breast-cancer, and severity is moderate on failure count alone. Neither termination carried an efficacy archetype, one being a shift in standard of care and the other a company shutdown, so the Claidex record offers no evidence against this pathway. The flag is recorded for completeness rather than as a warning, and the question it raises is whether a docking-site inhibitor adds anything where ATP-competitive CDK4 and CDK6 inhibitors are already approved.

Abstract excerpt

The animal cell division cycle is initiated by the cyclin-dependent kinases CDK4 and CDK6 in complex with D-type cyclins. Cyclin D-CDK4/6 complex formation is promoted by the assembly factors p21 and p27, which bind both subunits. p27 binds the hydrophobic patch on cyclin D that is similar to the patch used by other cell cycle cyclins to dock their substrates. This raised the question as to how cyclin D could find its substrates if its hydrophobic patch were already occupied? Here, we show that D-type cyclins use their A2' helix to dock the retinoblastoma protein Rb, a key substrate regulating cell cycle progression. The specific interface of cyclin D's A2' helix is unique among cyclins and its mutation slows proliferation. Taken together, our work identifies a cyclin D-substrate docking mechanism that can be targeted by novel cancer therapeutics.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.