Nucleotide oligomerization domain (NOD)-like receptors (NLRs) are critical cytoplasmic pattern-recognition receptors (PRRs) that play an important role in the host’s innate immune response and immunity homeostasis. Additionally, Members of the NLRs act as important cellular sensors, where NLRP3 is involved in sensing the integrity of the cytoplasm and self-assembles in response to sterile injury. NLRP3 is s a component of the inflammasome that detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NLRP3 in turn triggers an immune response. Inappropriate activation of the NLRP3 inflammasome has been implicated in multiple inflammatory and autoimmune diseases.
GDC-2394 is an orally active and selective NLRP3 inhibitor.
From: Blevins HM, et al. Front Aging Neurosci. 2022 Jun 10;14:879021.
In THP-1 cells, GDC-2394 inhibits NLRP3-induced caspase-1 activity in a concentration-dependent manner but does not inhibit NLRC4-dependent inflammasome activation. Moreover, GDC-2394 inhibits NLRP3-induced apoptosis-associated speck-like protein containing CARD (ASC) speck formation in THP-1 cells. In addition, in mouse bone marrow-derived macrophages (BMDMs), GDC-2394 also blocks NLRP3-dependent IL-1β release. GDC-2394 inhibits the production of IL-1β in human and mouse whole blood after activation of the NLRP3 inflammasome with LPS and ATP. Meanwhile, it also inhibits the production of IL-1β in human whole blood after crystal activation of the NLRP3 inflammasome in a concentration-dependent manner. Furthermore, GDC-2394 inhibits the IL-1β and IL-18 production in stimulated human monocyte-derived macrophages. In an acute mouse peritonitis model, GDC-2394 (0.1-10 mg/kg; p.o.) results in a dose-dependent decrease in peritoneal IL-1β concentrations. Besides, GDC-2394 also reduces paw swelling and pain in a functional rat model of gouty arthritis.
Overall, GDC-2394 is an orally active and selective NLRP3 inhibitor with a potent anti-inflammatory effect.
 Christopher McBride, et al. J Med Chem. 2022 Nov 10;65(21):14721-14739.