Bicyclic DGK Inhibitors for Restoring T Cell Antitumor Immunity
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Solution Overview
Problem
Current immunotherapies for cancer, such as immune checkpoint inhibitors, face challenges with primary or acquired resistance, and overexpression of DGKα and DGKζ in tumor infiltrating lymphocytes suppresses T cell function, leading to immune evasion by cancer cells.
Innovation Solution
Development of bicyclic compounds that selectively inhibit diacylglycerol kinase (DGK)α and DGKζ, which are used in combination with current ICT therapies such as PD(L)-1 and CTLA4, can potentially restore antitumor immunity in subsets of patients who have primary or acquired immune resistance and are consequently refractory to current ICTs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immune checkpoint inhibitors are used to treat cancer, then T cell activity is restored, but primary or acquired resistance occurs in subsets of patients
Solution Approach 1:
The patent segments the DGK enzyme family into specific isoforms (DGKα and DGKζ) as distinct therapeutic targets. By developing inhibitors that selectively target these specific isoforms rather than using broad immunotherapy approaches, the treatment can address the specific molecular mechanism causing resistance in subsets of patients, thereby improving overall efficacy and adaptability across different patient populations
Solution Approach 2:
The patent changes the therapeutic parameter from blocking inhibitory molecules (checkpoint inhibitors) to directly inhibiting DGKα and DGKζ enzymes. This parameter change targets a different pathway in the immune suppression mechanism, allowing the treatment to overcome resistance that develops against checkpoint inhibitors by acting through a complementary molecular mechanism
2Object-affected harmful factors
If DGKα and DGKζ are overexpressed in tumor infiltrating lymphocytes, then T cell function is suppressed, but cancer cells evade immune surveillance
Solution Approach 1:
The patent converts the harmful overexpression of DGKα and DGKζ into a beneficial therapeutic target. By specifically inhibiting these enzymes that are overexpressed in tumor infiltrating lymphocytes, the treatment transforms the molecular mechanism of immune suppression into the very target that, when blocked, restores T cell function and enhances antitumor immunity
Solution Approach 2:
The patent introduces bicyclic compound inhibitors as intermediary molecules that mediate between the overexpressed DGKα/DGKζ enzymes and the T cell function. These small molecule intermediaries bind to and inhibit the DGK enzymes, thereby indirectly restoring T cell activity without directly manipulating the T cells themselves
3Reliability
If bicyclic compounds inhibit DGKα and DGKζ, then T cell activation is enhanced, but direct effects on cancer proliferation may occur
Solution Approach 1:
The patent merges two therapeutic mechanisms into a single treatment approach: enhancing T cell activation through DGK inhibition and directly affecting cancer cell proliferation through the same DGKα/DGKζ inhibition. This dual action merges immune-mediated antitumor activity with direct antiproliferative effects, potentially providing synergistic benefits
Data Source
AI summary
The present application provides bicyclic compounds that modulate the activity of diacylglycerol kinase (DGK), which are useful in the treatment of various diseases, including cancer.