Seviteronel Dexamethasone Composition Metalloenzyme Selectivity

Solution Overview

Problem

Current metalloenzyme inhibitors face challenges in achieving a balance between potency and selectivity, leading to clinical toxicity due to indiscriminate binding to off-target enzymes, which affects the treatment of diseases such as prostate cancer and breast cancer.

Innovation Solution

The use of a pharmaceutical composition comprising seviteronel and dexamethasone, administered in specific dosage ranges, to target metalloenzymes effectively while minimizing adverse effects on related enzymes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If a tightly binding metal-binding group is utilized to increase potency, then enzyme inhibition potency is improved, but selectivity for the target enzyme versus related metalloenzymes deteriorates

Engineering Contradiction:

Improveenzyme inhibition potencyVSAvoidselectivity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing metal-binding groups with specific spatial and electronic characteristics tailored to the target enzyme's active site geometry. The metal-binding group is positioned and structured to match the local environment of the target metalloenzyme, creating a fit that is highly specific to that enzyme while maintaining strong binding. This local optimization allows potent inhibition without indiscriminate binding to other metalloenzymes.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent utilizes parameter changes by systematically varying the metal-binding group's chemical properties (such as binding affinity, coordination geometry, and electronic characteristics) to achieve the optimal balance between potency and selectivity. By adjusting these parameters, the invention creates metal-binding groups that bind tightly enough to effectively inhibit the target enzyme but with sufficient discrimination to avoid off-target effects.

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If a weakly binding metal-binding group is utilized to improve selectivity, then selectivity for the target enzyme is improved, but potency is suboptimal

Engineering Contradiction:

ImproveselectivityVSAvoidenzyme inhibition potency

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent applies local quality by designing metal-binding groups with specific spatial and electronic characteristics tailored to the target enzyme's active site geometry. The metal-binding group is positioned and structured to match the local environment of the target metalloenzyme, creating a fit that is highly specific to that enzyme while maintaining strong binding. This local optimization allows potent inhibition without indiscriminate binding to other metalloenzymes.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent utilizes parameter changes by systematically varying the metal-binding group's chemical properties (such as binding affinity, coordination geometry, and electronic characteristics) to achieve the optimal balance between potency and selectivity. By adjusting these parameters, the invention creates metal-binding groups that bind tightly enough to effectively inhibit the target enzyme but with sufficient discrimination to avoid off-target effects.

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If indiscriminate binding to off-target metalloenzymes occurs, then broad enzyme coverage is achieved, but clinical toxicity increases

Engineering Contradiction:

Improvebroad enzyme coverageVSAvoidclinical toxicity

Core Design Contradiction:

Adaptability or versatilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing metal-binding groups with specific spatial and electronic characteristics tailored to the target enzyme's active site geometry. The metal-binding group is positioned and structured to match the local environment of the target metalloenzyme, creating a fit that is highly specific to that enzyme while maintaining strong binding. This local optimization allows potent inhibition without indiscriminate binding to other metalloenzymes.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent applies blessing in disguise by converting the general property of metal binding (which could cause off-target effects) into a selective advantage. By carefully designing the metal-binding group's characteristics, the invention transforms what could be a source of toxicity (broad metal binding) into a tool for selective inhibition. The metal-binding group is designed to exploit specific features of the target enzyme's active site, turning potential harm into therapeutic benefit.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS11980626B2Compositions for treatment of breast and prostate cancer

Publication Date: 2024.05.14 KEMBI THERAPEUTICS PTY LTD

AI summary

The instant invention describes pharmaceutical compositions and dosing regimens comprising seviteronel and/or dexamethasone, and methods of treating diseases, disorders or symptoms thereof.