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GABP bioPROTAC
- Development stage
- Preclinical
- Lead developer
- University of California, San Francisco
- Modality
- Fc-Fusion Proteins → Carrier/Scaffold Proteins → Recombinant Proteins and Enzymes, PROTACs (E3 ligase recruitment) → Targeted Protein Degraders (TPDs) → Small Molecules, Bivalent/Multivalent Binders → Multivalent & Scaffold-Based Small Molecules → Small Molecules
01
Overview
GABP bioPROTAC is an AI-engineered biological proteolysis-targeting chimera (bioPROTAC) designed to selectively degrade the GA-binding protein alpha (GABPA) subunit. GABPA is a transcription factor that specifically activates the mutant telomerase reverse transcriptase (TERT) promoter, a common driver of cellular immortality in various cancers, including glioblastoma, oligodendroglioma, medulloblastoma, and high-grade meningioma. The drug was developed using in silico protein-protein interaction modeling via AlphaFold to identify a minimal GABPB domain capable of binding GABPA, which was then fused with an E3 ubiquitin ligase. By depleting GABPA protein, the bioPROTAC eliminates GABPA binding to the mutant TERT promoter, leading to epigenetic silencing (reduction of H3K4me3 and increase of H3K27me3 marks) and a significant reduction in TERT expression. Preclinical studies in orthotopic xenograft models of glioblastoma have demonstrated that GABP bioPROTAC can reduce tumor growth and improve survival by reversing tumor cell immortality in a promoter mutation-specific manner.
- Other names
- GABPA bioPROTAC
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