HDAC Inhibitors Modulate MDSC Phenotype to Enhance Anti-Tumor Immunity
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Solution Overview
Problem
Current anti-tumor therapies face challenges in effectively addressing immune suppression mediated by myeloid-derived suppressor cells (MDSCs), which hinder the immune response against tumors and contribute to cancer progression and metastasis.
Innovation Solution
Development of novel compounds that target MDSC-mediated immune suppression by enhancing anti-tumor immune responses, inhibiting key receptors such as EGFR, HER2, and XIAP, and inducing apoptosis in cancer cells, thereby preventing tumor escape from immunosurveillance and metastasis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current anti-tumor therapies are used, then tumor growth can be inhibited, but MDSC-mediated immune suppression persists and hinders effective anti-tumor immune response
Solution Approach 1:
The patent uses HDAC inhibitors as intermediary compounds that mediate between the tumor microenvironment and the immune system. These compounds modulate MDSC function by inhibiting histone deacetylase activity, thereby converting the harmful immune-suppressive environment into a more immunoreactive state without directly attacking tumor cells
Solution Approach 2:
The invention changes the biochemical parameters of MDSCs by altering histone acetylation status through HDAC inhibition. This parameter change transforms MDSCs from an immune-suppressive phenotype to a phenotype that supports anti-tumor immunity, addressing the contradiction between maintaining tumor inhibition and eliminating immune suppression
2Productivity
If single receptor inhibition is used, then specific signaling pathways can be blocked, but simultaneous inhibition of multiple receptors is needed to enhance activity and prevent resistance
Solution Approach 1:
The patent merges multiple therapeutic functions into a single compound class (HDAC inhibitors) that can simultaneously address multiple pathways. These compounds concurrently inhibit MDSC-mediated suppression and modulate tumor cell receptors, effectively combining what would traditionally require multiple separate therapies
Solution Approach 2:
HDAC inhibitors exhibit multi-functionality by simultaneously affecting MDSCs, tumor cells, and the broader tumor microenvironment. A single compound class performs multiple therapeutic roles: modulating immune cell function, inhibiting tumor growth, and preventing metastasis, thereby simplifying the treatment regimen while maintaining high productivity
Data Source
AI summary
The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, tautomers, stereoisomers, solvates, hydrates, polymorphs, and compositions thereof. Also provided are methods and kits involving the inventive compounds for treating proliferative diseases (e.g., cancers (e.g., breast cancer, prostate cancer, lung cancer, and ovarian cancer), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound of the invention may enhance the anti-tumor immune response by inhibiting or eliminating the immune suppression mediated by immune suppressor myeloid cells (MDSCs), inducing apoptosis, and/or inhibit or down-regulate proteins (e.g., epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), X-linked inhibitor of apoptosis protein (XIAP), and heat shock protein 90 (Hsp90)) in the subject.