Can PROTACs truly become oral drugs?

Oral delivery remains one of the most challenging objectives in proteolysis-targeting chimera (PROTAC) development. Although a growing number of PROTACs are administered orally in clinical studies, and several have demonstrated measurable systemic exposure and pharmacodynamic activity (such as ARV-110, ARV-471, and BMS-986365), the ability to reliably design PROTACs with predictable oral bioavailability remains limited. This article sheds light on the limitations of current design paradigms, the field's heavy reliance on cereblon-based chemistry, and the complex interplay of conformation, polarity, efflux, and solubility that shapes a PROTAC's behavior, emphasizing the importance of chameleonicity and conformational folding. We argue that the field will benefit greatly from adopting an 'oral-first' conformation-centric approach, discovering new E3 ligases and ligands, earlier predictive modeling, and strategic formulation technologies. Progressing alternative modalities in parallel might further expand opportunities for developing orally viable protein-elimination therapies.