Singleton SUMOylation Inhibitors Targeting E1 Enzymes
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Solution Overview
Problem
Current therapies for cancer, particularly colorectal cancer, have limited effectiveness due to radioresistance associated with elevated levels of SUMOylation enzymes, necessitating the development of novel inhibitors to enhance the sensitivity of cancer cells to genotoxic stress.
Innovation Solution
Development of small molecule SUMOylation inhibitors, specifically targeting SUMO E1 enzymes, which inhibit the SUMOylation process without affecting ubiquitination pathways, thereby sensitizing cancer cells to radiation and chemotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cancer therapies are used, then treatment is provided, but cancer cells exhibit radioresistance due to elevated SUMOylation enzyme levels
Solution Approach 1:
The patent extracts and specifically targets the SUMOylation pathway from the complex cellular protein modification system. By designing inhibitors that selectively bind to SUMO E1 enzymes (SAE1/SAE2) and block SUMOylation without affecting ubiquitination pathways, the invention isolates and counteracts the specific mechanism responsible for radioresistance, thereby improving treatment effectiveness while minimizing off-target effects
Solution Approach 2:
The invention changes the biochemical parameter of protein modification by blocking SUMOylation. The small molecule inhibitors alter the activity state of SUMO E1 enzymes, preventing the formation of SUMO-conjugated proteins. This parameter change (from active SUMOylation to inhibited SUMOylation) sensitizes cancer cells to radiation and chemotherapy, overcoming radioresistance
2Reliability
If SUMOylation inhibitors are developed to overcome radioresistance, then cancer cell sensitivity to treatment is enhanced, but potential toxicity to normal cells may increase
Solution Approach 1:
The patent applies local quality by creating inhibitors with selective action on cancer cells. The small molecule compounds are designed to target SUMO E1 enzymes specifically in the context of cancer cell physiology, where elevated SUMOylation enzyme levels create a vulnerable state. Normal cells with baseline SUMOylation levels maintain essential functions, creating a therapeutic window that limits toxicity while enhancing cancer cell sensitivity
Solution Approach 2:
The invention employs partial action by using inhibitors at concentrations and dosages that achieve sufficient SUMOylation blockade in cancer cells without causing complete inhibition in normal cells. The selective toxicity arises because cancer cells, with their already elevated SUMOylation activity, are more dependent on this pathway for survival and radioresistance, making them more susceptible to partial inhibition
Data Source
AI summary
According to the embodiments described herein, a SUMOylation inhibitor compound comprising a singleton scaffold is provided. In some embodiments, a method for inhibiting a SUMOylation enzyme in a cell is provided. Such a method may include administering a SUMOylation inhibitor compound to the cell. In some aspects, the SUMOylation enzyme is SUMO E1 or SUMO E2. In some aspects, the method may be used to inhibit a cancer cell in vitro (e.g., grown in culture) or in vivo (e.g., as part of a tumor in a subject). In other embodiments, a method for treating a cancer, degenerative diseases and viral infection is provided. Such a method may include administering an effective amount of a pharmaceutical composition to a subject having the cancer. The pharmaceutical composition may include a singleton SUMOylation inhibitor compound. In some embodiments, the method for treating a cancer may further comprise administering one or more DNA-damaging therapy in combination with administration of the pharmaceutical composition.