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Updated: Sep 7, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs)
Malte Arnold1, Temi Thompson2, Lorraine Glennie2
1Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany.
Abstract:
The dysregulation of CK1 isoforms is linked to various types of diseases, including neurodegeneration and different types of neoplasia such as colon, pancreatic, breast, and ovarian cancer. For CK1 isoforms, a plethora of effective small molecule inhibitors are available. However, only a few degraders of CK1α and, more recently, proteolysis targeting chimeras (PROTACs) for CK1δ/CK1ε have been reported. In this study, we applied the PROTAC concept by harnessing molecular modelling to design and synthesize a series of candidate CK1δ-targeting PROTACs based on a highly specific and potent benzothiazole-based CK1δ inhibitor that we previously developed in our lab. In the present study, we established a modular synthetic platform to systematically generate a set of PROTAC degrader candidates consisting of the CK1δ-specific inhibitor scaffold, alkyl and PEG linker motifs with various lengths, and Cereblon (CRBN)-engaging pomalidomide and thalidomide derivatives as E3 ligase binders. We demonstrate that several PROTACs degrade CK1δ/ε in various cells. The most potent PROTAC P1d inhibits the phosphorylation of downstream substrates through CK1δ/ε degradation. We establish the requirement of CUL4ACRBN and the proteasome for the P1d-mediated degradation of CK1δ/ε.
Insights
Researchers developed novel proteolysis targeting chimeras (PROTACs) to degrade Casein Kinase 1 delta/epsilon (CK1δ/ε). The most effective PROTAC, P1d, successfully degraded CK1δ/ε and inhibited downstream signaling, requiring CUL4A-CRBN and the proteasome.
Area of Science:
- Biochemistry and Molecular Biology
- Medicinal Chemistry
- Cancer Research
Background:
- Dysregulation of Casein Kinase 1 (CK1) isoforms is implicated in neurodegeneration and various cancers.
- While CK1 inhibitors are abundant, targeted degraders like proteolysis targeting chimeras (PROTACs) for CK1δ/ε are scarce.
Purpose of the Study:
- To design and synthesize novel CK1δ-targeting PROTACs using molecular modeling.
- To establish a modular platform for generating diverse PROTAC candidates.
- To evaluate the efficacy of these PROTACs in degrading CK1δ/ε and inhibiting downstream signaling.
Main Methods:
- Utilized molecular modeling to design CK1δ-targeting PROTACs based on a benzothiazole inhibitor scaffold.
- Employed a modular synthetic platform incorporating variable linkers and Cereblon (CRBN)-binding moieties (pomalidomide/thalidomide derivatives).
- Assessed CK1δ/ε degradation in cells and measured downstream substrate phosphorylation inhibition.
Main Results:
- Successfully synthesized and characterized several PROTACs capable of degrading CK1δ/ε in various cell types.
- The most potent PROTAC, P1d, effectively degraded CK1δ/ε and inhibited downstream substrate phosphorylation.
- Demonstrated that P1d-mediated degradation is dependent on CUL4ACRBN and the proteasome.
Conclusions:
- Developed effective CK1δ/ε-targeting PROTACs through rational design and modular synthesis.
- P1d represents a promising chemical probe for studying CK1δ/ε function and a potential therapeutic lead.
- The study highlights the utility of PROTAC technology for targeted protein degradation in disease contexts.
