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Published on: November 9, 2020
Selective CDK6 Degradation via the KLHDC2 E3 Ubiquitin Ligase
Eunhye Jeon1,2, Younghoon Kim1, Hyunwoo Ahn3
1Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
None:
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.
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