Selective CDK6 Degradation via the KLHDC2 E3 Ubiquitin Ligase

We discovered novel small molecule ligands of KLHDC2 and leveraged them to generate KLHDC2-mediated CDK6-selective degraders. Degrader <b>48a</b> exhibited potent and selective CDK6 degradation (DC₅₀ = 0.037 μM) over CDK4 (DC₅₀ > 10 μM) in MOLM-14 cells, leading to pronounced G₀/G₁ cell-cycle arrest and apoptosis through inhibition of CDK6 downstream signaling. In addition, <b>48a</b> demonstrated superior growth-inhibitory activity compared to the warhead, palbociclib, in several leukemia cells and displayed favorable microsomal stability. Proteomic profiling confirmed that <b>48a</b> selectively degrades CDK6 with minimal effects on other CDK family members. Furthermore, <b>48a</b> reduced tumor burden and CDK6 levels in an in vivo xenograft model. Collectively, these findings highlight the potential of KLHDC2-mediated degraders as a novel strategy for selective CDK6 degradation and underscore the promise of KLHDC2 as an alternative E3 ligase platform for targeted protein degradation.