Regulated Induced Proximity Targeting Chimeras (RIPTACs): a Novel Heterobifunctional Small Molecule Therapeutic...

Area of Science:

• Oncology
• Drug Discovery
• Molecular Biology

Background:

• Targeting intracellular proteins for cancer therapy remains a challenge.
• Existing therapies like ADCs cannot target intracellular proteins.
• Proteolysis Targeting Chimeras (PROTACs) enable protein proximity induction.

Approach:

• Developed novel heterobifunctional molecules called Regulated Induced Proximity Targeting Chimeras (RIPTACs).
• RIPTACs form a stable ternary complex between a cancer-specific target protein and a pan-expressed essential protein.
• This induces a cooperative protein:protein interaction (PPI) that abrogates the essential protein's function.

Key Points:

• RIPTACs leverage differentially expressed intracellular proteins, expanding targetable space.
• This approach can overcome non-target resistance mechanisms by targeting essential protein inactivation.
• Demonstrated RIPTACs with covalent/non-covalent ligands targeting HaloTag7-FKBP, inducing anti-proliferative response.

Conclusions:

• RIPTACs represent a novel therapeutic modality for cancers with selectively expressed intracellular proteins.
• This strategy offers a new avenue for precision oncology drug discovery.
• RIPTACs induce selective cancer cell death through targeted protein inactivation.