Undruggable Drugs

Hannah sets the stage by introducing the concept of 'undruggable drugs', referring to proteins, protein families, or pieces of RNA that are notoriously hard to target in drug discovery. J. Bradner elaborates on the shifting definitions in this category, explaining that while certain proteins were previously deemed undruggable, new methodologies and technologies are emerging to tackle these challenges. This includes understanding the intricacies of cellular pathways and the activities of proteins that can lead to diseases, especially in the context of cancer.

Bradner discusses how the advent of innovative technologies and tools is revolutionizing drug discovery. The conversation highlights the importance of looking beyond traditional methods—where researchers typically hunted for molecules to fit into specific protein pockets. New approaches, such as targeting allosteric sites or utilizing molecular glues, enable scientists to engage with previously considered undruggable proteins, thus enhancing therapeutic potential and understanding of complex disease mechanisms.

The episode delves into the concept of molecular glues, which are designed to bind two proteins that don't usually interact, effectively short-circuiting disease pathways. These breakthroughs allow researchers to target proteins in new, impactful ways. Furthermore, the philosophy behind targeted protein degradation is addressed, showcasing how scientists can not only inhibit but potentially eliminate problematic proteins that contribute to disease.

The importance of translating laboratory research into effective treatments for patients is a major theme in this episode. Bradner emphasizes the necessity of rigorous basic research in disease biology, as well as early-stage clinical trials that help refine and repurpose drug concepts. He notes that creating viable medicines involves navigating challenges in manufacturing and delivery, particularly for advanced therapies that may require complex logistics.

Looking ahead, Bradner highlights the exciting potential for future therapies through advanced gene editing technologies, hybrid gene therapies, and novel drug delivery methods. He contemplates the possibilities of engineering solutions that can efficiently address a range of diseases and what role companies like Novartis can play in making these innovations accessible and practical for patients across the globe.