Year: 2026
Type: article
Abstract: High Resolution Image Download MS PowerPoint Slide PROTACs are commonly developed by linking E3 ligase-recruiting ligands to established inhibitors of a protein target, often resulting in degraders that retain enzymatic inhibition. Type II inhibition of cyclin-dependent kinases (CDKs) has been challenging, as reported compounds generally exhibit weak biochemical potency and limited cellular activity. Consistent with these limitations, most reported CDK degraders have been derived from type I ATP-competitive inhibitors. Here, we explored whether targeted protein degradation could enable functional CDK targeting from a type II kinase scaffold. Using the multikinase inhibitor regorafenib as a starting scaffold, we generated a focused library of CRL4 CRBN -recruiting bifunctional molecules and profiled their degradation activity using quantitative mass spectrometry-based proteomics. This analysis unexpectedly revealed CDK5 and CDK6, kinases not inhibited by the parent scaffold, as degradation targets. Optimization of this series led to JHK-02–108–2, a selective CDK6 degrader that does not display a hook effect and promotes potent CDK6 degradation despite weak CDK6 binding and negligible CDK6 inhibition. In cellular models of acute myeloid leukemia (AML) and glioblastoma, JHK-02–108–2 induced sustained G1 arrest and reduced phosphorylation of the retinoblastoma protein. Interestingly, subtle modifications in PROTAC architecture redirected degradation selectivity, yielding JHK-02–102–1 as a selective type II CDK5 degrader derived from the same scaffold. Together, these findings establish the first type II inhibitor-derived selective CDK6 degrader and demonstrate that targeted protein degradation can enable functional CDK targeting from type II kinase scaffolds.
DOI: 10.1021/jacs.6c10277
Authors: Ji Hyeon Kim, Caitlin E. Mills, Zuzanna Kozicka, Daniel C. Scott, Cyrus Jin, Zixuan Jiang, Brendan G. Dwyer, Qixiang Geng, Sean T. Toenjes, Woong Sub Byun, Dina ElHarouni, Hongyu Li, Keith L. Ligon, Abby M. Thornhill, Hannah M. Jones, Bryan A. Romero, Stephen M. Hinshaw, Benjamin L. Ebert, Brenda A. Schulman, Katherine A. Donovan, Eric S. Fischer, Nathanael S. Gray
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: Howard Hughes Medical Institute, Sanofi, St. Jude Children's Research Hospital, American Lebanese Syrian Associated Charities, Broad Institute, National Research Foundation, École Polytechnique Fédérale de Lausanne, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Dongguk University, National Research Foundation of Korea, Max-Planck-Gesellschaft, Astellas Pharma, Ministry of Science and ICT, South Korea, National Institutes of Health, School of Medicine, Stanford University, University at Buffalo, School of Humanities and Sciences, Stanford University, Department of Systems Biology, Harvard Medical School, National Cancer Institute, Stanford Cancer Institute
Awards: G1605099728, G3730575107, G3939613512, 500 MHz NMR Spectrometer System with High Sensitivity Cryoprobe and Automated Sample Changer for Biochemical Research, G4950536974, Elucidation of protein degradation machinery for transcription factor dependencies in acute myeloid leukemia, G7691710229, G9000137291, G9000238948, The molecular basis of IMiD induced neo-substrate recruitment to the CRL4CRBN ubiquitin E3 ligase, Development of a generalizable chemo-proteomics screening platform for small molecule degraders applied to HDACs
OpenAlex ID: W7166129635