From biologics to small-molecule modulators: the evolving landscape of interleukin-targeted therapeutics

The interleukin (IL) family, a crucial class of cytokines in immune regulation, orchestrates diverse biological processes, including immune response modulation, lymphocyte proliferation/differentiation and pathological mechanisms underlying autoimmune disorders, inflammatory diseases and cancers. Building on this mechanistic foundation, biologic drugs such as monoclonal antibodies targeting ILs and their receptors have achieved significant success. Although developing low-molecular-weight compounds to target the protein-protein interaction interfaces of ILs and their receptors remains challenging, an increasing number of successful cases demonstrate that such a small-molecule strategy is feasible, which has sparked growing interest. In this comprehensive review, we discuss the biological functions of various IL family members, present representative small-molecule drugs targeting ILs and summarize current progress as well as future strategies for developing new small-molecule modulators of ILs.