Reverse-Mode ATP Synthase Inhibitors for Glycolytic Cancer Selectivity
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Solution Overview
Problem
Existing polyketide F1F0 ATP synthase inhibitors, such as oligomycin, are toxic to both cancer and normal cells, lacking a therapeutic window and being ineffective against glycolytic cancers, while prior art suggests compounds targeting the forward mode of ATP synthase as anti-cancer therapeutics, which is also crucial for normal cell function.
Innovation Solution
Development of compounds that selectively inhibit the reverse mode of ATP synthase, specifically inhibiting F1F0 ATP hydrolysis, to target cancer cells without harming normal cells, even under normoxic conditions, and enhance metabolic efficiency in normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If polyketide F1F0 ATP synthase inhibitors (e.g., oligomycin) are used to inhibit ATP synthase, then ATP production is blocked, but both cancer and normal cells are toxicized with no therapeutic window
Solution Approach 1:
The patent applies local quality by making the inhibitor selective for the reverse mode of ATP synthase in cancer cells while sparing the forward mode in normal cells. This is achieved through compounds that specifically bind to and inhibit the ATP-hydrolysing reverse mode, creating a localized effect that differentiates between cancer and normal cell metabolism without broadly toxicizing all cells.
Solution Approach 2:
The patent inverts the conventional approach by targeting the reverse mode (ATP hydrolysis) rather than the forward mode (ATP synthesis) of ATP synthase. This inversion allows selective inhibition of cancer cell metabolism while preserving normal cell function, as normal cells primarily operate in forward mode while cancer cells rely on reverse mode operation.
2Reliability
If forward mode of ATP synthase is inhibited to target cancer cells, then cancer cell ATP production is blocked, but normal cell function is also impaired
Solution Approach 1:
The patent inverts the conventional approach by targeting the reverse mode (ATP hydrolysis) rather than the forward mode (ATP synthesis) of ATP synthase. This inversion allows selective inhibition of cancer cell metabolism while preserving normal cell function, as normal cells primarily operate in forward mode while cancer cells rely on reverse mode operation.
3Object-affected harmful factors
If compounds are designed to kill cancer cells selectively, then therapeutic window is improved, but effectiveness against glycolytic cancers with Warburg effect is reduced
Solution Approach 1:
The patent applies parameter changes by modifying the metabolic state of cancer cells through reverse mode inhibition, which forces even glycolytic cancers to rely more on oxidative phosphorylation. This parameter change in metabolic flux makes glycolytic cancers susceptible to the inhibitor, as they must increase their reliance on the forward mode and OXPHOS to compensate for the blocked reverse mode, thereby creating therapeutic vulnerability.
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
The compounds effectively kill glycolytic cancer cells, including those with the Warburg effect, while maintaining normal cell function and metabolic efficiency, and can enhance the efficacy of conventional therapies by reducing their side effects.
Implementation Method 1
compounds that preferentially inhibit the ATP-hydrolysing mode of ATP synthase
Data Source
AI summary
Compounds of the following formula, and pharmaceutically-acceptable salts, solvates, hydrates and prodrugs thereof, formula (A) are useful to preferentially inhibit the ATP-hydrolysing mode of ATP synthase, and are thereby useful for treating various diseases and orders including cancer, particularly cancers that utilise the Warburg effect.