A natural product-derived degrader (COT-01): cortisone-based CRBN recruitment for cyclin D2 degradation in multiple myeloma.

Overexpression of Cyclin D2 drives aberrant cell cycle progression in multiple myeloma (MM). However, its lack of intrinsic enzymatic activity renders it an "undruggable" target for conventional small-molecule inhibitors. Here, we report the identification of COT-01, a natural product-derived cortisone analog, as a CRBN-dependent molecular glue degrader of Cyclin D2. COT-01 exhibited CRBN-binding activity with an apparent IC50 of 2.5 μM in an HTRF-based competitive assay, and BLI analysis independently supported concentration-dependent binding of COT-01 to recombinant human CRBNmidi, with a kinetic KD of 28.6 μM. COT-01 induced significant G0/G1 phase arrest and apoptosis in MM cells. Targeted proteomic profiling identified Cyclin D2 as one of the most significantly downregulated proteins among those analyzed following COT-01 treatment. Mechanistically, COT-01 facilitated the depletion of Cyclin D2 protein levels in a time- and dose-dependent manner without altering its mRNA levels, suggesting a post-translational degradation mechanism. Molecular modeling suggested that the cortisone scaffold of COT-01 engages the ligand-binding pocket of CRBN, while the biochemical and cellular findings support its classification as a molecular glue degrader. Furthermore, in a xenograft mouse model, intraperitoneal administration of COT-01 significantly suppressed tumor growth without significant changes in tumor-free body weight or terminal liver and kidney weights. These findings support further evaluation of COT-01 as a CRBN-dependent molecular glue degrader targeting Cyclin D2 in multiple myeloma.