Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Immunomodulatory imide drugs (IMiDs) are key E3 ligase ligands for proteolysis targeting chimeras (PROTACs).
• IMiD neo-substrates like Ikaros and Aiolos are often considered off-targets in PROTAC development.
• Degrading these neo-substrates offers potential for synergistic multi-protein degradation.

Purpose of the Study:

• To develop a novel PROTAC (ALV-07-082-03) targeting CDK4/6 and Helios simultaneously.
• To investigate the therapeutic potential of cotargeting CDK4/6 and Helios.
• To explore the redirection of IMiD neo-substrate specificity using alternative molecular glues.

Main Methods:

• Design and synthesis of a novel IMiD-based PROTAC (ALV-07-082-03) conjugating palbociclib (CDK4/6 inhibitor) with a Helios degrader (DKY709).
• Pharmacological evaluation of the triple degrader in cancer cells.
• Assessment of downstream signaling suppression, proliferation inhibition, and IL-2 secretion.

Main Results:

• ALV-07-082-03 effectively achieved pharmacological codegradation of CDK4/6 and Helios.
• The triple degrader potently suppressed downstream signaling pathways and cancer cell proliferation.
• Enhanced derepression of Interleukin-2 (IL-2) secretion was observed.

Conclusions:

• Demonstrated the successful development of a triple degrader by incorporating alternative molecular glue ligands for PROTACs.
• Showcased the synergistic effects of cotargeting CDK4/6 and Helios.
• Highlighted the potential of rationally redirecting PROTAC neo-substrate specificity for enhanced therapeutic outcomes.