Conquering PROTAC molecular design and drugability

PROTACs are reshaping drug discovery by enabling targeted protein degradation, overcoming the limitations of traditional inhibitors, and addressing previously “undruggable” proteins. The present perspective explores advancements in PROTAC molecular design, focusing on ligand discovery, E3 ligase recruitment, and ternary complex optimization. Integrating AI-driven modeling, FBDD, and SBDD accelerates PROTAC development. In contrast, emerging innovations, such as PHOTACs, hypoxia-responsive systems, and Ab-PROTACs, enhance precision and reduce systemic toxicity. Clinical successes, including ARV-110 for castration-resistant prostate cancer and ARV-471 for breast cancer, exemplify their ability to overcome resistance and provide durable effects. PROTACs are expanding into neurodegenerative diseases and rare conditions, highlighting their versatility. By addressing challenges in pharmacokinetics, safety, and scalability, PROTACs are poised to revolutionize precision medicine. This article presents a forward-looking perspective on conquering the molecular design and drugability of PROTACs, paving the path for transformative therapies.