Bridging the Gap: How Pre-Formulation and Strategies Enable Scalable PROTAC Development

Since their initial publication in 2001, proteolysis-targeting chimeras (PROTACs) have rapidly progressed from an academic concept to a promising new therapeutic modality (1). Over the past two decades, they’ve captured the imagination of researchers for their potential to tackle disease-causing proteins that have long been considered “undruggable” using conventional small molecules.

Today, numerous companies are advancing PROTAC candidates from preclinical and early clinical stages to later phases of development, reflecting growing confidence in this emerging field (2). Yet translating PROTACs from the bench to the bedside involves more than innovative biology. It requires a robust, multidisciplinary framework, especially in pre-formulation and analytical development, to manage their unique complexities as drug molecules.

The Challenge of the ‘Undruggable’ Proteome

Despite decades of advances in small molecule and biologics-based therapies, the vast majority of disease-relevant proteins remain out of reach. An estimated 93% of the human proteome cannot be targeted using traditional drug discovery methods (3). This includes proteins such as transcription factors, scaffolding molecules, and mutant oncogenes that play critical roles in disease but lack the features necessary for conventional ligand binding.