Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs)

Arnold, Malte; Thompson, Temi; Glennie, Lorraine; Hollnagel, Mattes; Sapkota, Gopal; Peifer, Christian

doi:10.3390/molecules30224452

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Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs)

by

Malte Arnold

¹

,

Temi Thompson

²,

Lorraine Glennie

²,

Mattes Hollnagel

¹,

Gopal Sapkota

^2,*

and

Christian Peifer

^1,*

¹

Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Christian-Albrechts-University of Kiel, 24118 Kiel, Germany

²

MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK

^*

Authors to whom correspondence should be addressed.

Molecules 2025, 30(22), 4452; https://doi.org/10.3390/molecules30224452

Submission received: 27 October 2025 / Revised: 13 November 2025 / Accepted: 14 November 2025 / Published: 18 November 2025

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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 CUL4A^CRBN and the proteasome for the P1d-mediated degradation of CK1δ/ε.

Keywords: PROTACs; protein degradation; CK1δ; kinases; cancer therapy

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MDPI and ACS Style

Arnold, M.; Thompson, T.; Glennie, L.; Hollnagel, M.; Sapkota, G.; Peifer, C. Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs). Molecules 2025, 30, 4452. https://doi.org/10.3390/molecules30224452

AMA Style

Arnold M, Thompson T, Glennie L, Hollnagel M, Sapkota G, Peifer C. Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs). Molecules. 2025; 30(22):4452. https://doi.org/10.3390/molecules30224452

Chicago/Turabian Style

Arnold, Malte, Temi Thompson, Lorraine Glennie, Mattes Hollnagel, Gopal Sapkota, and Christian Peifer. 2025. "Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs)" Molecules 30, no. 22: 4452. https://doi.org/10.3390/molecules30224452

APA Style

Arnold, M., Thompson, T., Glennie, L., Hollnagel, M., Sapkota, G., & Peifer, C. (2025). Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs). Molecules, 30(22), 4452. https://doi.org/10.3390/molecules30224452

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Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs)

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