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RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor.

ABSTRACT: The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory, metabolic and neurodegenerative diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. RRx-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials, but its effects on inflammatory diseases are not known. Here, we show that RRx-001 is a highly selective and potent NLRP3 inhibitor that has strong beneficial effects on NLRP3-driven inflammatory diseases. RRx-001 inhibits the activation of the canonical, noncanonical, and alternative NLRP3 inflammasomes but not the AIM2, NLRC4 or Pyrin inflammasomes. Mechanistically, RRx-001 covalently binds to cysteine 409 of NLRP3 via its bromoacetyl group and therefore blocks the NLRP3-NEK7 interaction, which is critical for the assembly and activation of the NLRP3 inflammasome. More importantly, RRx-001 treatment attenuates the symptoms of lipopolysaccharide (LPS)-induced systemic inflammation, dextran sulfate sodium (DSS)-induced colitis and experimental autoimmune encephalomyelitis (EAE) in mice. Thus, our study identifies RRx-001 as a new potential therapeutic agent for NLRP3-driven diseases.

SUBMITTER: Chen Y

PROVIDER: S-EPMC8166941 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor.

Chen Yun Y He Hongbin H Lin Bolong B Chen Yun Y Deng Xianming X Jiang Wei W Zhou Rongbin R

Cellular & molecular immunology 20210510 6

The NLRP3 inflammasome plays a crucial role in innate immune-mediated inflammation and contributes to the pathogenesis of multiple autoinflammatory, metabolic and neurodegenerative diseases, but medications targeting the NLRP3 inflammasome are not available for clinical use. RRx-001 is a well-tolerated anticancer agent currently being investigated in phase III clinical trials, but its effects on inflammatory diseases are not known. Here, we show that RRx-001 is a highly selective and potent NLRP ...[more]

PMID: 33972740

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Project description:Chronic unresolving inflammation is emerging as a key underlying pathological feature of many if not most diseases ranging from autoimmune conditions to cardiometabolic and neurological disorders. Dysregulated immune and inflammasome activation is thought to be the central driver of unresolving inflammation, which in some ways provides a unified theory of disease pathology and progression. Inflammasomes are a group of large cytosolic protein complexes that, in response to infection- or stress-associated stimuli, oligomerize and assemble to generate a platform for driving inflammation. This occurs through proteolytic activation of caspase-1-mediated inflammatory responses, including cleavage and secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and initiation of pyroptosis, an inflammatory form of cell death. Several inflammasomes have been characterized. The most well-studied is the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome, so named because the NLRP3 protein in the complex, which is primarily present in immune and inflammatory cells following activation by inflammatory stimuli, belongs to the family of nucleotide-binding and oligomerization domain (Nod) receptor proteins. Several NLRP3 inflammasome inhibitors are in development, all with multi-indication activity. This review discusses the current status, known mechanisms of action, and disease-modifying therapeutic potential of RRx-001, a direct NLRP3 inflammasome inhibitor under investigation in several late-stage anticancer clinical trials, including a phase 3 trial for the treatment of third-line and beyond small cell lung cancer (SCLC), an indication with no treatment, in which RRx-001 is combined with reintroduced chemotherapy from the first line, carboplatin/cisplatin and etoposide (ClinicalTrials.gov Identifier: NCT03699956). Studies from multiple independent groups have now confirmed that RRx-001 is safe and well tolerated in humans. Additionally, emerging evidence in preclinical animal models suggests that RRx-001 could be effective in a wide range of diseases where immune and inflammasome activation drives disease pathology.

Project description:IntroductionThe current standard of care for newly diagnosed glioblastoma (GBM) is maximum surgical resection followed by concurrent treatment with temozolomide (TMZ) and radiotherapy (RT) and then six to twelve cycles of maintenance TMZ. RRx-001, an NLRP3 inhibitor and nitric oxide (NO) donor with chemoradiosensitizing, vascular normalizing and macrophage repolarizing properties, is currently in a Phase III trial for small cell lung cancer (SCLC). The purpose of this non-randomized trial was to establish the safety and look for a signal of clinical activity of RRx-001 as an add-on to RT and TMZ in patients with newly diagnosed glioblastoma.MethodsIn this non-randomized, open-label, two part trial called G-FORCE-1 (NCT02871843), the first four cohorts of adult patients with histologically confirmed high grade gliomas received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and escalating doses of once weekly RRx-001 from 0.5 mg to 4 mg according to a 3+3 design followed by a 6 week no treatment interval and then standard maintenance TMZ (150 mg/m2 Cycle 1 and 200 mg/m2 in subsequent cycles) until disease progression. The second two cohorts of patients received fractionated radiotherapy (60 Gy in 30 fractions over 6 weeks), daily 75 mg/m2 temozolomide and once weekly RRx-001 4 mg followed by a 6 week no treatment interval and then two different maintenance schedules until disease progression according to the same 3+ 3 design: 1. 0.5 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapy; 2. 4 mg RRx-001 once weekly + 100 mg/m2 TMZ 5 days/week for up to 6 cycles of therapyThe primary endpoint was the recommended dose/maximally tolerated dose of the combination of RRx-001, TMZ and RT. Secondary endpoints were overall survival, progression free survival, objective response rate, duration of response and clinical benefit response.ResultsA total of 16 newly diagnosed glioblastoma patients were enrolled. No dose limiting toxicities were observed and no MTD was reached. The recommended dose is 4 mg. After 24 months of follow up the median OS was 21.9 months (95% CI: 11.7 - NA). PFS median was 8 months (95% CI: 5 - NA). The overall response rate was 18.8% (3 PR out of 16) and the disease control rate was 68.8% (3 PR, 8 SD out of 16).ConclusionsThe addition of RRx-001 to TMZ and RT and to TMZ during maintenance was safe and well-tolerated and deserves further study.

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RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor.

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RRx-001 ameliorates inflammatory diseases by acting as a potent covalent NLRP3 inhibitor.

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