Linker Design Principles in PROTACs Influencing Ternary Complex Stability for Prostate Cancer

Overview

Hormone-driven cancers, such as prostate cancer, rely on hormone receptor signaling for growth and survival. While hormone deprivation therapies are initially effective, prolonged treatment often leads to resistance. Proteolysis-targeting chimeras (PROTACs) offer a promising strategy by selectively degrading hormone receptors via the ubiquitin-proteasome system; however, effective linker design remains a key challenge. This study examines how systematic modification of linker length, polarity, and orientation in androgen receptor-targeting PROTACs incorporating a novel biguanide-derived linker influences ternary complex stability. Molecular dynamics simulations reveal that increasing linker length enhances ligand stability and binding strength, while increased polarity reduces predicted binding strength. Additionally, comparison of ortho- and para-linked designs reveals that attachment geometry significantly impacts structural stability, with the orientation of the ortho-linked designs introducing less variability and para-linked designs introducing greater variability. These results support a dual-action therapeutic strategy and establish design principles showing that linker length and geometry primarily determine ternary complex stability, whereas increased polarity weakens binding. This provides a framework for effective optimization of next-generation PROTAC therapeutics for prostate cancer.

Competition history

• CSEF 2026 Biochemistry/ Molecular Biology (Senior Division) · Entry S-04-16

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