Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are critical cytoplasmic pattern-recognition receptors (PRRs). They play an important role in the host’s innate immune response and immunity homeostasis. Among them, NLRP3 belongs to the NLR subfamily. NLRP3 is a component of the innate immune system that functions as a pattern recognition receptor (PRR). In addition, NLRP3 together with the adaptor ASC protein PYCARD forms a caspase-1 activating complex known as the NLRP3 inflammasome. Moreover, NLRP3 inflammasome activation plays a critical role in inflammation-related disorders. Furthermore, the NLRP3 inflammasome pathway involves two key stages: priming and activation. First, the priming stage consists of transcriptional upregulation of NLRP3 and pro-IL-1β through activation of the NF-κB pathway. In the second stage, NLRP3 is activated via one or more mechanisms, such as K⁺ efflux, lysosomal resident cathepsin B, ROS, and ubiquitin/deubiquitination modification.

NIC-0102 is a potent and orally active proteasome inhibitor that specifically inhibits NLRP3 inflammatory vesicle activation.

From: Wu X, et al. J Med Chem. 2022 Sep 22;65(18):11985-12001.

NIC-0102 induces the accumulation of polyubiquitinated NLRP3 and blocks the assembly and activation of the NLRP3 inflammasome. Meanwhile, this compound has no effect on NLRC4 or AIM2 inflammasomes. In addition, NIC-0102 interferes with the NLRP3-ASC interaction and blocks ASC oligomerization. Moreover, NIC-0102 exhibits inhibitory effects on NF-κB in the priming step of the NLRP3 pathway in LPS-primed J774A.1 cells. It inhibits the NF-κB subunit p65, as well as phosphorylates p65 and NLRP3 protein, at which NF-κB-dependent TNF-α secretion is slightly decreased. Unexpectedly, NIC-0102 also inhibits the production of pro-IL-1β. Also, NIC-0102 has a good pharmacokinetic profile. Importantly, NIC-0102 shows potent anti-inflammatory effects in a model of dextran sulfate sodium-induced ulcerative colitis. Thus, NIC-0102 has the potential for inflammatory disease research.

Taken together, NIC-0102 is a potent and orally active proteasome inhibitor, that specifically inhibits NLRP3 inflammasome activation, with anti-inflammation activity.

Reference:

[1] Xinyi Wu, et al. J Med Chem. 2022 Sep 22;65(18):11985-12001.