OLT1177, a β-sulfonyl nitrile molecule, is a selective inhibitor of the NLRP3 inflammasome, with unique properties to reverse the metabolic costs of inflammation and to treat IL-1β– and IL-18–mediated diseases.
NLRP3 inflammasome can be widely found in epithelial cells and immune cells. The NOD-like receptors (NLRs) family member NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain which facilitates self-oligomerization and has ATPase activity[1]. Dapansutrile（OLT1177） is a potent, selective and orally active inhibitor of NLRP3 inflammasome. Anti-inflammatory, analgesic activity[2]. OLT1177 specifically inhibited both canonical and noncanonical NLRP3 inflammasome activation in vitro, and showed no effect on the AIM2 and NLRC4 inflammasomes. OLT1177 reduced caspase-1 activity and IL-1β production in monocytes from patients with CAPS and alleviated the severity of LPS-induced systemic inflammation in vivo. Importantly, no biochemical or hematological adverse effects were observed in humans receiving a high concentration of OLT1177 for 8 days. Like CY-09, OLT1177 exerts its anti-inflammatory effect on NLRP3 inflammasome activation independently of signal 1 (NLRP3 and pro-IL-1β expression) or K+ efflux,but directly binds to NLRP3 and inhibits ATPase activity[3]. In vivo, tumor-associated NLRP3/IL-1 signaling induced expansion of myeloid-derived suppressor cells (MDSCs), leading to reduced natural killer and CD8+ T cell activity concomitant with an increased presence of regulatory T (Treg) cells in the primary tumors. Either genetic or pharmacological inhibition of tumor-derived NLRP3 by dapansutrile (OLT1177) was sufficient to reduce MDSCs expansion and to enhance antitumor immunity, resulting in reduced tumor growth[4].
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