A Type II CDK6 Degrader Enables Cellular Targeting beyond the Limits of Type II Inhibition
Ji Hyeon Kim1, Caitlin E Mills2, Zuzanna Kozicka3,4,5
1Department of Chemical and Systems Biology, ChEM-H, and Stanford Cancer Institute, Stanford School of Medicine, Stanford University, Stanford, California 94305, United States.
Journal of the American Chemical Society
|June 26, 2026
Summary
This study introduces novel Proteolysis Targeting Chimeras (PROTACs) derived from type II kinase inhibitors. These PROTACs effectively degrade CDK5 and CDK6, enabling targeted protein degradation for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Targeted protein degradation using PROTACs is a promising therapeutic strategy.
- Developing type II kinase inhibitors for cyclin-dependent kinases (CDKs) has been challenging due to low potency and cellular activity.
- Most existing CDK degraders are based on type I inhibitors.
Purpose of the Study:
- To investigate the potential of type II kinase scaffolds for targeted protein degradation of CDKs.
- To develop novel PROTACs targeting CDK5 and CDK6.
- To evaluate the efficacy of these degraders in cancer models.
Main Methods:
- Utilized regorafenib as a starting scaffold to create a library of CRL4CRBN-recruiting bifunctional molecules.
- Employed quantitative mass spectrometry-based proteomics to profile degradation activity.
- Tested lead compounds in cellular models of acute myeloid leukemia (AML) and glioblastoma.
Main Results:
- Identified CDK5 and CDK6 as unexpected degradation targets from the type II scaffold.
- Developed JHK-02-108-2, a selective CDK6 degrader with potent degradation despite weak inhibition, and JHK-02-102-1, a selective type II CDK5 degrader.
- Demonstrated that JHK-02-108-2 induces G1 arrest and reduces retinoblastoma protein phosphorylation in cancer cells.
Conclusions:
- Established the first type II inhibitor-derived selective CDK6 degrader.
- Showcased that targeted protein degradation can enable functional CDK targeting from type II kinase scaffolds.
- Highlighted the potential of PROTACs for developing novel cancer therapeutics targeting CDKs.
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