PROTACs and Glues: Striking Perspectives for Engineering Cancer Therapy À La Carte.

Abstract

PROTACs are bifunctional small molecules that simultaneously bind a target protein and a component of the ubiquitin-proteasome system, thereby inducing selective degradation of the target. They represent a class of compounds capable of achieving the complete elimination of disease-relevant proteins. Molecular glues, by contrast, enhance existing surface complementarity between an E3 ligase and a target protein, promoting its ubiquitination and subsequent degradation. Both approaches are at the forefront of current efforts to overcome the long-standing challenge of undruggable tumor targets. In this context, AI-based strategies offer a powerful means to accelerate the discovery, optimization, and production of highly selective protein binders, streamlining access to potent degraders and maximizing therapeutic potential. These capabilities open new horizons for targeting a wide spectrum of previously inaccessible molecular pathways involved in cancer progression. Altogether, these advances position PROTACs and molecular glues as transformative agents for personalized oncology, particularly within the emerging paradigm of molecular tumor boards, where tailored therapeutic decisions and tumor-adapted drugs could be made rapidly accessible for a given patient.