Unravelling the potential of small molecule tumor necrosis factor-α (TNF) inhibitors: A comprehensive review

TNF-α is a key cytokine, plays a critical role in the pathogenesis of autoimmune and inflammatory diseases such as rheumatoid arthritis and psoriasis. As a result, TNF-α has emerged as a pivotal therapeutic target. Currently, monoclonal antibodies and decoy receptors targeting TNF-α are widely used, yet they face limitations such as administration challenges. These drawbacks have driven the exploration of small molecule inhibitors as alternative therapeutic agents due to their oral bioavailability, ability to cross biological barriers, and cost-effective production. Significant efforts have been directed toward developing small-molecule TNF-α inhibitors, which function either by disrupting the TNF trimer or by blocking TNF-αTNFR interactions. Several candidates have progressed to clinical trials, demonstrating their potential as therapeutic agents. This review provides a comprehensive overview of TNF-α small-molecule inhibitors, covering their discovery, design strategies, structure-activity relationships, and biological evaluation. Additionally, it discusses current clinical outcomes and outlook to guide researchers in the drug design and development of more potent inhibitors.