SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases.

New therapeutic approaches for chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis are needed because current treatments are often suboptimal in terms of both efficacy and the risks of serious adverse events. Inhibitor of apoptosis proteins (IAPs) are E3 ubiquitin ligases that inhibit cell death pathways and are themselves inhibited by second mitochondria-derived activator of caspases (SMAC). SMAC mimetics (SMs), small-molecule antagonists of IAPs, are being evaluated as cancer therapies in clinical trials. IAPs are also crucial regulators of inflammatory pathways because they influence both the activation of inflammatory genes and the induction of cell death through the receptor-interacting serine-threonine protein kinases (RIPKs), nuclear factor κB (NF-κB)-inducing kinase, and mitogen-activated protein kinases (MAPKs). Furthermore, there is an increasing interest in specifically targeting the substrates of IAP-mediated ubiquitylation, especially RIPK1, RIPK2, and RIPK3, as druggable nodes in inflammation control. Several studies have revealed an anti-inflammatory potential of RIPK inhibitors that either block inflammatory signaling or block the form of inflammatory cell death known as necroptosis. Expanding research on innate immune signaling through pattern recognition receptors that stimulate proinflammatory NF-κB and MAPK signaling may further contribute to uncovering the complex molecular roles used by IAPs and downstream RIPKs in inflammatory signaling. This may benefit and guide the development of SMs or selective RIPK inhibitors as anti-inflammatory therapeutics for various chronic inflammatory conditions.