Proximity Inducers in Drug Discovery - A Perspective on Cooperativity

Proximity inducing drugs offer transformative therapeutic opportunities by precisely controlling protein interactions and/or protein modulations including targeted protein degradation. PROTACs, prominent in this field, successfully degrade previously undruggable proteins like transcription factors by engaging both target proteins and E3 ligases. Despite their modular design however, PROTACs face challenges due to large molecular size, lipophilicity, poor bioavailability, and toxicity. Molecular glues present a promising alternative, overcoming these limitations with smaller size and improved bioavailability. Yet, identifying and optimizing glues is more challenging, as their binding interactions are still unpredictable. In this case study, Dr. Hans-Jörg Roth, former director at Novartis Global Discovery Chemistry, emphasizes optimizing cooperativity — boosting target affinity via chaperone proteins — as the key to developing smaller, highly selective, and safer proximity-inducing therapeutics.