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

TY - JOUR

T1 - Design and Synthesis of Novel Candidate CK1δ Proteolysis Targeting Chimeras (PROTACs)

AU - Arnold, Malte

AU - Thompson, Temi

AU - Glennie, Lorraine

AU - Hollnagel, Mattes

AU - Sapkota, Gopal

AU - Peifer, Christian

N1 - Copyright: © 2025 by the authors.

PY - 2025/11/17

Y1 - 2025/11/17

N2 - 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.

AB - 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.

KW - cancer therapy

KW - CK1δ

KW - kinases

KW - PROTACs

KW - protein degradation

UR - https://www.scopus.com/pages/publications/105022887147

U2 - 10.3390/molecules30224452

DO - 10.3390/molecules30224452

M3 - Article

C2 - 41302507

AN - SCOPUS:105022887147

SN - 1420-3049

VL - 30

JO - Molecules

JF - Molecules

IS - 22

M1 - 4452

ER -