SUMO E1 Inhibitor Compounds for Selective Covalent Cancer Therapy
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Solution Overview
Problem
Aberrations in post-translational modification of cellular proteins by the small ubiquitin-like modifier (SUMO) family of proteins are associated with the pathogenesis of life-threatening diseases such as cancer, neurodegenerative disorders, and viral infection, with enzymes catalyzing SUMO-modification being present in higher levels in cancer tissues and playing a crucial role in cancer proliferation and metastasis.
Innovation Solution
Development of compounds capable of inhibiting the E1 enzyme, which catalyzes SUMO-modification, to target cancer therapeutics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If SUMO-modification enzymes (E1) are targeted for cancer treatment, then cancer proliferation and metastasis can be inhibited, but the complexity of developing specific inhibitors increases
Solution Approach 1:
The patent applies parameter changes by systematically varying chemical parameters of the inhibitor molecules, including substituent groups (R1-R30), ring structures (ring A), and electrophilic moieties (E). This allows optimization of binding affinity and selectivity for the E1 enzyme while managing development complexity through structured chemical modification approaches.
Solution Approach 2:
The inhibitor compounds are segmented into distinct functional components: a core structure (ring A), substituent groups (R1-R30), and electrophilic moieties (E). This segmentation enables independent optimization of each component's contribution to enzyme inhibition, facilitating systematic drug development.
2Reliability
If E1 enzyme is inhibited to address SUMO-modification aberrations, then cancer-related pathogenesis can be addressed, but potential off-target effects and toxicity increase
Solution Approach 1:
The patent applies local quality by creating highly specific inhibitor structures with particular electrophilic moieties (E) and substituent patterns that target the E1 enzyme's active site with high precision. This localized specificity minimizes off-target effects while maintaining strong inhibitory activity against the cancer-relevant E1 enzyme.
Solution Approach 2:
The patent replaces non-specific enzymatic inhibition with a more precise covalent bonding mechanism through electrophilic moieties that form specific chemical bonds with the E1 enzyme's catalytic residues. This substitution provides more controllable and selective inhibition, reducing off-target effects compared to non-specific inhibitors.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Inhibiting the E1 enzyme effectively addresses the aberrations in SUMO-modification, providing a potential therapeutic approach for cancer treatment.
Implementation Method 1
E is an electrophilic moiety, selected from: -C(=O)CH=CH2, -C(=O)-ethynyl, -C(=O)CH=CHCF3, -C(=O)CH=CHCHF2, -C(=O)CH=CHCH2F, and -C(=O)CH2Br
Data Source
AI summary
The present invention relates to compounds and compositions capable of acting as inhibitors of small ubiquitin-like modifier (SUMO) family of proteins. The compounds and compositions may be used in the treatment of cancer. There are disclosed, inter alia, methods of inhibiting an E1 enzyme, and compounds useful for inhibiting an E1 enzyme.