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 48a 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, 48a demonstrated superior growth-inhibitory
activity compared to the warhead, palbociclib, in several leukemia
cells and displayed favorable microsomal stability. Proteomic profiling
confirmed that 48a selectively degrades CDK6 with minimal
effects on other CDK family members. Furthermore, 48a 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.