ENPP1 Inhibitor Binding to Extracellular Zn2+ Domain
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Solution Overview
Problem
Current ENPP1 inhibitors are ineffective at physiological pH, which is crucial for treating diseases associated with ENPP1 activity in various tissues, as they are typically tested and optimized for higher pH conditions.
Innovation Solution
Development of compositions containing specific compounds that inhibit ENPP1's activity by binding to its extracellular domain, particularly with two Zn2+ ions, which are effective at physiological pH and can be administered through various routes to modulate ENPP1 signaling and activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If assays are performed at pH 9 to accelerate the assay process, then the assay speed is improved, but the inhibitor effectiveness deteriorates at physiological pH conditions
Solution Approach 1:
The patent applies parameter changes by developing inhibitors with optimized chemical structures that maintain effectiveness across different pH conditions. The compounds are designed to be active at physiological pH (7.4-7.5) rather than requiring alkaline conditions (pH 9), thereby resolving the contradiction between assay speed and inhibitor effectiveness at physiological pH.
2Quantity of substance
If existing ENPP1 inhibitors are used, then the compound availability is improved, but the treatment effectiveness at physiological pH deteriorates
Solution Approach 1:
The patent provides specific chemical compounds with defined structures (Formulae I-IX) that are designed to be effective at physiological pH. These new compounds replace existing inhibitors that only work at alkaline pH, thereby improving treatment effectiveness while maintaining compound availability through defined chemical structures and synthesis methods.
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 inhibit ENPP1's enzymatic activities, including phosphodiester and pyrophosphate bond cleavage, at physiological pH, enhancing treatment options for diseases related to ENPP1 in various tissues such as cancer and other disorders.
Implementation Method 1
the ENPP1 inhibitor binds to the extra-cellular domain of ENPP1, containing an active site with two Zn2+ ions
Data Source
AI summary
Compositions for inhibiting ENPP1 signaling, inactivity, and/or activity are disclosed. The compositions contain a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt thereof. Preferably, the compound binds to the active site of ENPP1 on the extra-cellular domain of ENPP1. Also described are methods of using the compositions. The compounds can be administered via one or more routes of administration to a subject in need thereof. The compounds are present in amounts effective to treat, prevent, or reduce one or more diseases or disorders associated with ENPP1 signaling, inactivity, and/or activity.