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

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 CUL4A^CRBN 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.