Small-molecule modulators of the necroptotic pathway: A medicinal chemistry perspective

Necroptosis, a regulated form of programmed necrosis mediated by the RIPK1/RIPK3/MLKL signaling pathway, plays a pivotal role in the pathogenesis of diverse diseases, including neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, infections, and cancer. This review comprehensively summarizes the significant progress in developing small-molecule modulators targeting core components of the pathway. It systematically details the classification, mechanisms of action, and SAR of RIPK1, RIPK3, and MLKL inhibitors and inducers. Notably, Several RIPK1 inhibitors (e.g., DNL-788, DNL-758, R-552) have advanced to Phase II clinical trials for indications like multiple sclerosis, ulcerative colitis, and rheumatoid arthritis. Despite these advancements, the field continues to face challenges, particularly the need for chemical scaffold design and therapeutic strategies to address two longstanding challenges: off-target effects and enhancing blood-brain barrier (BBB) penetration. This review systematically summarizes the development history of regulators targeting this pathway, covering emerging multitarget inhibitors, bifunctional molecules, and AI-driven drug design progress, laying an important foundation for related drug discovery research.