Abstract 4366666: Selective Degradation of NIMA-related kinase 7 (NEK7) via a Molecular Glue Degrader Inhibits IL-1 Downstream of NLRP3 Inflammasome Activation: A Novel Therapeutic Approach for Cardiovascular Inflammation

Abstract

Background: Inhibition of IL-1 is a safe and effective treatment of recurrent pericarditis. However, the currently available agents are administered subcutaneously and there are no approved IL-1-directed oral therapies. NEK7 is a key component of the NLRP3 inflammasome, which drives inflammation through release of IL-1. MRT-8102 is a first-in-class oral molecular glue degrader (MGD) designed to selectively eliminate NEK7 and thereby reduce IL-1-mediated inflammation. MRT-8102 therefore offers a novel investigational approach to targeting inflammatory cardiovascular diseases (CVD). Objectives: To evaluate the potential therapeutic activity of MGD-mediated degradation of NEK7 using preclinical models in mice and non-human primates (NHPs). In addition, to assess the impact of NEK7 degradation on NLRP3 inflammasome activation within in vitro and ex vivo systems. Methods: IL-1β response was evaluated in a mouse model of sterile peritonitis, representing acute innate immune activation relevant to CVD. NEK7 levels and NLRP3-driven IL-1β response were measured in PBMCs from NHPs dosed orally with MRT-8102 once a day for 5 days, followed by ex vivo stimulation with LPS and nigericin. In vitro assays with human whole blood from obese donors, as wells as human monocyte-derived macrophages, were used to assess inflammasome assembly and cytokine release. Results: Proteomic and crystallographic studies confirmed that MRT-8102 forms a selective ternary complex with NEK7 and cereblon, with no identified off-target effects. In a mouse peritonitis model, MRT-8102 led to dose-dependent inhibition of IL-1β and TNF-α in peritoneal fluid and plasma, along with reductions in other inflammatory cytokines. In a NHP multi-dose model, MRT-8102 reduced NEK7 levels by 85%, with near-complete suppression of IL-1β ex vivo. In an ex vivo stimulation model using blood from obese human donors (BMI > 30), and similarly in vitro using human monocyte-derived macrophages, MRT-8102 suppressed IL-1β more potently than a benchmark NLRP3 inhibitor. Conclusion: Our studies indicate that MRT-8102 is a potent, selective NEK7 degrader that inhibits NLRP3-driven activity including cytokine release in vivo and in vitro. Therefore, the NEK7-targeting MGD, MRT-8102, holds promise as a novel therapeutic for the treatment of CVD driven by chronic innate immune activation.