Discovery of Highly Potent and Orally Available CCNK Molecular Glue Degraders as Broad-Spectrum Antitumor Agents

Cyclin K (CCNK) has been identified as a promising antitumor target. However, the existing CCNK degraders have the defect of metabolic instability, which hinders their development as antitumor agents. Using a metabolically oriented scaffold hopping strategy based on HQ461 and NCT02, we developed ZLY025─a highly potent CCNK degrader (DC₅₀ = 42.7 nM, Dmax >93%). It exhibits broad-spectrum antitumor activity, high kinase selectivity, excellent metabolic stability, and favorable oral pharmacokinetics (T_1/2 = 6.82 h). Moreover, ZLY025 induced the highly selective degradation of CCNK with low off-target degradation effects in TMT-based global proteomic analysis. In the xenografted model, ZLY025 exerted robust antitumor activity by effectively degrading CCNK. In the subacute toxicity study, ZLY025 exhibited adequate safety profiles even at the sustaining high dose of 200 mg/kg. Based on these positive results, ZLY025 is worthy of further evaluation as the first highly potent and orally available CCNK molecular glue degrader.