Targeting the IL-23-IL-23R Interface with Small Molecules: Challenges, Opportunities, and Emerging Strategies

Interleukin-23 (IL-23) is a validated therapeutic driver in psoriasis and inflammatory bowel disease, and selective IL-23p19 antibodies have established a high efficacy benchmark for pathway inhibition. Interest has therefore expanded toward oral, non-antibody approaches, including IL-23R-targeting macrocyclic peptides and conventional low-molecular-weight compounds. Direct antagonism of the IL-23p19-IL-23R interface is attractive because it acts upstream of intracellular JAK2/TYK2 signaling and is structurally separated from the p40-IL-12Rβ1 interaction shared with IL-12. The principal challenge is medicinal-chemical: the orthosteric site is a dynamic proteinprotein interaction surface with limited constitutive pocket character. This Mini-Review focuses on the evidence relevant to drug discovery rather than reiterating pathway biology. We distinguish experimentally validated interface binders from computationally prioritized candidates, summarize potency, selectivity, assay format and development status where available, and discuss lessons from program attrition. Recent advances include an induced orthosteric pocket on IL-23p19, live-cell competition pharmacology, highly potent oral IL-23R peptides, and early small molecule hits supported by cellular assays. Computational docking, molecular dynamics, MM/GBSA, QSAR, and AI-assisted design can enrich hypotheses but do not, by themselves, establish direct binding, selectivity, pharmacokinetics, or safety. The key unresolved question is whether a classical small molecule can demonstrate direct target engagement at this challenging interface while achieving sufficient potency, pathway selectivity, and drug-like exposure to compete with advanced biologic and peptide modalities.