Methods and compositions for inhibiting the NLRP3 inflammasome and/or LON protease

Inventors

Sporn, Michael B.

Assignees

Triterpenoid Therapeutics Inc

Abstract

The present invention relates to methods, compositions, and combinations for inhibiting the NLRP3 inflammasome and/or LON protease as well as methods, compositions, and combinations for treating cancer, particularly blood cancer or brain cancer. In certain aspects, the compositions and combinations include a synthetic triterpenoid, such as 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole (“CDDO-2P-Im”) and 1-[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-3-yl)-1H-imidazole (“CDDO-3P-Im”).

Core Innovation

The disclosure describes synthetic triterpenoid imidazoles, including CDDO-2P-Im and CDDO-3P-Im, as inhibitors of the NLRP3 inflammasome and/or the mitochondrial LON protease (LONP1). It links therapy resistance in cancers to NLRP3 activation and to LONP1-mediated stress adaptation and mitophagy, with suppression of inflammasome signaling as a central mechanistic rationale. In this context, the compounds are presented as agents that inhibit NLRP3 inflammasome activity and/or LON protease activity in a patient.

The disclosed therapeutic strategy targets cancers described as multiple myeloma and glioblastoma, including glioma more broadly, by administering CDDO-2P-Im in an amount effective to inhibit NLRP3 inflammasome and/or LON protease activity. The patent narrative further relates radiation therapy and chemotherapy resistance to NLRP3 activation and mitochondrial stress adaptation, positioning inflammasome inhibition as part of an anti-cancer effect. The disclosure includes both mechanistic readouts such as suppression of IL-1β/caspase-1 activation in inflammasome assays and functional anti-tumor outcomes.

The disclosure also provides combination regimens in which CDDO-2P-Im is used together with additional cancer therapies, including proteasome inhibitors (such as ixazomib) and chemotherapy agents described as temozolomide (TMZ) and platinum compounds (including cisplatin and oxaliplatin). The stated combination goals include enhancing cancer cell death, reducing therapy resistance, and reducing treatment-associated adverse effects that are described for TMZ (lymphopenia) and for proteasome inhibitors (neuropathic pain). Exposure and anti-tumor activity are reported in included examples, including effects in glioblastoma models and cisplatin-resistant ovarian cancer cell lines.

Claims Coverage

The independent claims cover three method categories (glioma-specific and broader cancer indications) that share a common inventive core: administering CDDO-2P-Im in an amount effective to inhibit NLRP3 inflammasome and/or LON protease activity. Across the independent claims, the inventive features are directed to specified cancer indications (glioma subtypes and additional cancers) and to regimen refinements affecting co-therapy and side-effect outcomes.

Across the independent claims, the central inventive concept is administering CDDO-2P-Im in an amount effective to inhibit NLRP3 inflammasome and/or LON protease activity, applied to treating glioma (including specified glioma types in dependent claims) and, in a broader independent framework, cancers including glioma, multiple myeloma, or ovarian cancer.

Stated Advantages

Documented Applications