Targeting Gasdermin for Management of Inflammatory Diseases and Cancer

Background

Inflammation is a key factor in numerous diseases, including sepsis, inflammatory bowel disease, Alzheimer’s disease, and cancer. Millions worldwide are affected by these conditions, with sepsis affecting over 49 million people annually and Alzheimer’s impacting more than 50 million individuals globally. Additionally, there is a critical unmet need in developing new cancer therapies, particularly for solid tumors that do not respond well to current immunotherapies. The market for treatments targeting inflammation and cancer is substantial, with billions of dollars spent each year. Existing treatments, such as anti-inflammatory drugs like NSAIDs and corticosteroids, and cancer therapies like checkpoint blockade (CPB) and chimeric antigen receptor T cell (CAR-T) therapies, have limitations, including significant side effects and a limited scope of efficacy. Therefore, there is a significant opportunity to develop therapies that more precisely target the underlying biological processes in these diseases.

Technology Overview

The innovative compounds described in this invention target gasdermin for multiple indications within inflammatory diseases and cancer.

Treatment of inflammatory diseases:

Our compounds represent a novel class of anti-inflammatory agents that function by inhibiting gasdermin-mediated pyroptosis and modulating cytokine release. They work directly on cysteine residues in inflammatory signaling molecules to inhibit caspase activity, offering targeted intervention in the inflammasome pathway. Proof-of-concept studies have demonstrated a reduction in inflammatory markers and improved outcomes in preclinical models, indicating their potential effectiveness in managing inflammation more precisely and with fewer side effects than current treatments.

Treatment of cancer:

The invention centers on the identification of small molecule compounds, specifically a quinoxaline derivative known as DMB (6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline), that act as direct and selective agonists for gasdermin D (GSDMD). Unlike traditional methods which require cleavage for activation, DMB activates GSDMD without cleavage, inducing pyroptosis in tumor cells without harming immune cells. This results in suppressed tumor growth and provides protective immunity, as demonstrated in mouse tumor models. DMB-treated cancer cells have shown to induce immunogenic cell death, leading to protection in secondary tumor challenges. Studies reveal that DMB synergizes with anti-PD-1 therapy and does not elevate proinflammatory cytokines or leukocyte count, indicating a reduced risk of systemic side effects.

Applications

• Inflammatory Diseases: Effective management for conditions like sepsis, arthritis, gout, and inflammatory bowel disease.
• Cardiovascular Diseases: Potential treatment for stroke, myocardial infarction, and heart failure.
• Metabolic and Neurodegenerative Diseases: Applications in diabetes, Alzheimer's, Parkinson's, and multiple sclerosis.
• Cancer Treatment: Targeting various solid tumors, particularly those unresponsive to current immunotherapies, and enhancing checkpoint inhibitors.
• Combination Therapies: Amplification of antitumor effects and stimulation of immune memory when combined with other cancer treatments.

Advantages

• Targeted Approach: Direct interaction with inflammasome components and activation of GSDMD offers focused anti-inflammatory and antitumor effects.
• Reduced Side Effects: Lower risk of gastrointestinal issues, immune suppression, and cytokine release syndrome compared to current NSAIDs, corticosteroids, and cancer therapies.
• Broad Therapeutic Potential: Applicable across multiple conditions where inflammation and tumor pyroptosis are key concerns.
• Innovation in Mechanism: Provides a novel mechanistic approach to treatment, addressing the root causes of inflammation and cancer cell growth rather than just symptoms.