From Large to Small Cytokine Receptor Antagonists

Here, we review general trends in biological and small molecule cytokine drug discovery, highlighting key learnings from two successful case studies (TNFα and IL-17), which have helped shape our understanding of how best to identify new small molecule cytokine antagonists. Over the past three decades, biological drugs have revolutionized the treatment of a wide range of diseases, from oncology to autoimmune diseases. Their ability to modulate extracellular targets, often inaccessible to conventional small molecule drugs due to their complex protein-protein interactions, has enabled the clinical validation of numerous novel cytokine targets. Despite their success, biological drugs have significant limitations. Challenges include poor oral bioavailability, tissue penetration and access to intracellular drug targets, as well as high manufacturing costs. These constraints have catalyzed efforts to develop small molecule equivalents that replicate the therapeutic efficacy of biologicals while overcoming their poor delivery and high production costs. Over the past twenty years, advances in structural biology, computational modeling, disease biology, hit-finding technologies, and medicinal chemistry have converged to collectively enable the identification and subsequent progression of small molecule cytokine modulators into clinical development. Looking ahead, we speculate on the future drug discovery landscape of this field with the likely emergence of small molecules drugs for a range of clinically validated cytokines like TSLP and TL1A. This evolution will be accelerated by the advent of novel modalities like extracellular degraders, oral peptide drugs and the development of next-generation biological drugs with multi-valency and improved delivery.