2. Academic Validation
  3. Selective CDK6 Degradation via the KLHDC2 E3 Ubiquitin Ligase

Selective CDK6 Degradation via the KLHDC2 E3 Ubiquitin Ligase

  • J Med Chem. 2025 Dec 11;68(23):25539-25568. doi: 10.1021/acs.jmedchem.5c02713.
Eunhye Jeon 1 2,  Younghoon Kim 1,  Hyunwoo Ahn 3,  Michael J Martinez 4,  Kyubin Hwang 1 2,  Soyeong Cho 3,  Brendan G Dwyer 4,  Bryan A Romero 4,  Stephen M Hinshaw 4,  Nathanael S Gray 4,  Taebo Sim 1 2 3 5
Affiliations

Affiliations

  • 1 Department of Biomedical Sciences, Graduate School of Medical Science, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
  • 2 Department of Medical Science, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
  • 3 Graduate School of Clinical Drug Discovery & Development, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
  • 4 Stanford Cancer Institute, Stanford School of Medicine, Stanford, California 94305, United States.
  • 5 Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
PMID: 41329866 DOI: 10.1021/acs.jmedchem.5c02713
Abstract

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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