Highlights
- MRT-8102 is an oral molecular-glue degrader that selectively targets NEK7 for proteasomal degradation and suppresses NLRP3 inflammasome activation in vitro and in vivo.
- Preclinical AHA 2025 data report blockade of pyroptotic membrane permeabilization, reduced multi-cytokine release, and stronger activity than a comparator small-molecule NLRP3 inhibitor in cholesterol crystal–induced assays relevant to atherosclerosis.
- In mouse and nonhuman primate models, MRT-8102 lowered IL-1β, caspase-1 activity and other inflammatory cytokines; a Phase 1 study in healthy volunteers and elevated‑risk individuals is underway with first human readouts expected in H1 2026.
Background: Why an upstream inflammasome approach matters in cardiometabolic disease
Inflammasome-driven innate immune signaling, especially via NLRP3 activation, is increasingly implicated in atherosclerosis, pericarditis, and related cardiometabolic disorders. Mechanistic and translational studies link cholesterol crystal–induced NLRP3 activation to IL-1β–mediated vascular inflammation and plaque progression (Duewell et al., Nature 2010), and large clinical trials have demonstrated that targeting the IL-1 pathway can reduce cardiovascular events (Ridker et al., NEJM 2017). Colchicine and IL-1 pathway biologics (e.g., canakinumab, rilonacept, anakinra) have shown benefits in selected settings, but limitations remain: injectable biologics raise adherence, cost and payer barriers; direct NLRP3 catalytic inhibitors are advancing but face selectivity, safety and route-of-administration challenges.
NEK7 (NIMA-related kinase 7) was identified as a necessary component of NLRP3 inflammasome assembly downstream of potassium efflux (Shi et al., Nature 2016). Inhibiting or removing NEK7 represents an upstream strategy that may simultaneously blunt inflammasome-driven cytokine release (IL-1β, IL-18) and pyroptotic cell death—both mechanistic contributors to plaque instability and acute pericardial flares.
Study design and preclinical program overview
The data presented by Monte Rosa Therapeutics at AHA 2025 consolidate cross-species pharmacology and mechanistic experiments for MRT-8102, an orally bioavailable molecular-glue degrader (MGD) designed to recruit NEK7 to an E3 ubiquitin ligase for targeted proteasomal degradation. The preclinical program described includes:
- In vitro assays in human monocyte-derived macrophages assessing NLRP3 activation, pyroptotic membrane permeabilization, and multi-cytokine release after canonical stimuli and cholesterol crystal challenge.
- Comparative potency assays versus a representative small-molecule NLRP3 inhibitor (referred to in the datasheet as selnoflast) in cholesterol crystal–induced inflammasome activation.
- A mouse peritonitis model assessing in vivo cytokine suppression (IL-1β, IL-1α, IL-6, TNF) following MRT-8102 dosing.
- Nonhuman primate pharmacodynamic assays: orally dosed cynomolgus monkeys with ex vivo whole-blood stimulation measuring IL-1β and caspase-1 activity.
- GLP toxicology packages examining systemic safety margins and pharmacokinetics to inform first-in-human dosing.
Key findings
The preclinical dataset emphasizes three linked domains: target engagement, inflammasome biology, and translational pharmacology.
Target engagement and selectivity
MRT-8102 produced robust, selective degradation of NEK7 across tested systems. The molecular-glue mechanism—binding NEK7 and bridging it to an E3 ligase—is intended to promote proteasomal degradation rather than enzymatic inhibition. According to the company’s poster and press materials, degradation was efficient and durable in both rodent and nonhuman primate matrices. Selectivity for NEK7 over related kinases was asserted in the preclinical characterization, a defining requirement for an upstream degrader to avoid on-target cell-cycle or mitotic perturbations attributable to NIMA kinase family biology.
Inflammasome suppression: cytokines, caspase-1 and pyroptosis
Functional readouts showed that NEK7 degradation suppressed canonical markers of NLRP3 activation. In human monocyte-derived macrophages, MRT-8102 blocked pyroptotic membrane permeabilization and reduced release of IL-1β and other proinflammatory cytokines. In a mouse peritonitis model, dosing produced reductions in IL-1β, IL-1α, IL-6 and TNF, consistent with upstream interference with inflammasome assembly and downstream cytokine cascades.
In cynomolgus monkeys given oral MRT-8102, ex vivo whole-blood stimulation yielded near-complete suppression of IL-1β and caspase-1 activity—an important translational signal because it demonstrates pharmacodynamic activity in a species with closer immune homology to humans.
Comparative potency in atherosclerosis-relevant assays
In cholesterol crystal–driven inflammasome assays, which model a key atherogenic stimulus identified in preclinical atherosclerosis studies (Duewell et al., Nature 2010), MRT-8102 reportedly delivered more potent suppression than a representative small-molecule NLRP3 inhibitor (company-reported comparator: selnoflast). This head-to-head in vitro signal is positioned as a differentiation point: by degrading an essential structural component required for NLRP3 assembly, MRT-8102 may achieve broader inhibition of both cytokine release and pyroptosis than catalytic inhibitors that block NLRP3 enzymatic activity alone.
Safety and toxicology
Monte Rosa’s GLP toxicology summary states a favorable safety window, citing exposures greater than projected human efficacious levels by >200-fold. That assertion supports first-in-human testing but requires cautious interpretation: preclinical windows do not always predict human safety, and degraders that recruit E3 ligases can carry off-target liabilities depending on ligase selection and tissue distribution.
Expert commentary and mechanistic perspective
The strategy to remove NEK7 as an upstream node is mechanistically persuasive. NEK7’s role in bridging potassium efflux to NLRP3 oligomerization makes it attractive as a choke point for inflammasome activation (Shi et al., Nature 2016). Removing NEK7 could theoretically suppress IL-1β and IL-18 while also preventing gasdermin D–dependent pyroptosis (Kayagaki et al., Nature 2015), which contributes to release of damage-associated molecular patterns and amplification of vascular inflammation.
That said, translational risks merit emphasis. Preclinical models—especially ex vivo whole-blood assays and acute peritonitis—are necessary but not sufficient to predict effects on chronic atherosclerotic plaque biology or recurrent pericarditis flares. Safety monitoring will be critical for infection risks and liver signals, which have emerged as concerns with some inflammasome-targeted programs. Additionally, degrader pharmacology introduces unique considerations: the magnitude and duration of protein knockdown, tissue distribution, potential for irreversible or long-lived effects in slowly dividing cells, and ligase-dependent off-target degradation must be tracked carefully in clinical development (see reviews on targeted protein degradation; Burslem & Crews, Nat Rev Drug Discov 2020).
Clinical development and operational implications
Monte Rosa has initiated a Phase 1 study (clinicaltrials.gov: NCT07119125) enrolling healthy volunteers and participants with elevated cardiovascular risk; initial readouts are expected in the first half of 2026. Near-term clinical end points will center heavily on biomarkers: quantitative NEK7 degradation (target engagement), ex vivo inflammasome stimulation assays, caspase-1 activity, and cytokine panels (IL-1β, IL-6, hsCRP), plus standard safety and PK assessments.
Operationally, trial sites and CROs will need immunology-capable central labs for caspase-1 and IL-1β assays and may require imaging resources (MRI/CT) if atherosclerosis endpoints are pursued. If recurrent pericarditis becomes the prioritized first patient population, investigators experienced with rilonacept and anakinra will be essential for enrollment and management of background therapy and washout periods.
Competitive landscape and strategic considerations
Monte Rosa is positioning MRT-8102 as an oral, once-daily entrant that could reduce payer and logistical friction relative to injectable IL-1/IL-6 biologics. However, the program competes with catalytic NLRP3 inhibitors and established cytokine blockers backed by robust clinical outcome data (e.g., canakinumab in CANTOS). Whether upstream NEK7 degradation translates into broader clinical benefit—by combining suppression of cytokine signaling and pyroptotic cell death—remains to be demonstrated in humans.
Limitations and unanswered questions
- Translatability from acute preclinical assays to chronic human cardiovascular disease is uncertain; atherosclerosis outcome signals require long follow-up and imaging or event-driven designs.
- Magnitude and durability of NEK7 knockdown in relevant tissues (vascular wall, pericardium) are unknown; blood-based PD may not fully reflect tissue effects.
- Potential off-target degradation and long-term safety of an oral degrader recruiting an E3 ligase require close surveillance.
- Comparator strategy in later trials (direct NLRP3 inhibitors, IL-1/IL-6 biologics, colchicine) will shape payer and regulatory perceptions of value.
Conclusion
MRT-8102 represents a mechanistically novel attempt to move upstream of cytokine blockade by degrading NEK7 to suppress NLRP3 inflammasome assembly and downstream pyroptosis. The AHA 2025 preclinical data are encouraging—showing cross-species target engagement, potent suppression of IL-1β and caspase-1, and promising comparative activity in cholesterol crystal assays relevant to atherosclerosis. The true test will be human pharmacodynamic translation, safety in at‑risk populations, and whether the strategy delivers clinically meaningful benefits compared with established cytokine blockers and catalytic NLRP3 inhibitors.
Funding and clinicaltrials.gov
The preclinical dataset and program development are reported by Monte Rosa Therapeutics. The Phase 1 study is registered on ClinicalTrials.gov under NCT07119125. Company disclosures in press materials and the AHA poster were used to compile the program summary.
Selected references
Duewell P, Kono H, Rayner KJ, et al. NLRP3 inflammasomes are required for atherogenesis triggered by cholesterol crystals. Nature. 2010;464(7293):1357–1361.
Shi H, Wang Y, Li X, et al. NLRP3 activation and cell death are regulated by the NEK7 kinase. Nature. 2016;530(7590):481–486.
Kayagaki N, Stowe IB, Lee BL, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526(7575):666–671.
Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017;377(12):1119–1131.
Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497–2505.
Klein AL, Imazio M, Cremer P, et al. Rilonacept for Recurrent Pericarditis. N Engl J Med. 2021;384(23):2319–2329.
Swanson KV, Deng M, Ting JP-Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19(8):477–489.
Burslem GM, Crews CM. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Nat Rev Drug Discov. 2020;19(9):615–637.
Monte Rosa Therapeutics press release and AHA 2025 poster (GlobeNewswire). Available: https://www.globenewswire.com/news-release/2025/11/08/3184076/0/en/Monte-Rosa-Therapeutics-Presents-Preclinical-Data-at-AHA-Scientific-Sessions-2025-on-the-Potential-of-MRT-8102-a-NEK7-directed-Molecular-Glue-Degrader-to-Treat-Cardiovascular-and-C.html
