Dimeric GYS1 Inhibitors for Selective Glycogen Reduction
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Solution Overview
Problem
Current treatments for diseases characterized by aberrant glycogen accumulation, such as Pompe disease, Cori disease, adult polyglucosan body disease, Lafora disease, and certain cancers, lack effective therapeutic interventions to reduce glycogen stores and improve patient outcomes.
Innovation Solution
Development of dimeric compounds that selectively inhibit glycogen synthase 1 (GYS1) enzyme activity, reducing tissue glycogen levels through glycogen substrate reduction therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If substrate reduction therapy is used to inhibit glycogen synthase, then tissue glycogen stores are reduced, but current treatments lack effectiveness in reducing glycogen stores and improving patient outcomes
Solution Approach 1:
The invention uses dimeric compounds consisting of two GYS1 inhibiting moieties connected by a linker. This segmentation approach creates a molecule with two active sites that can simultaneously bind to and inhibit GYS1 enzyme, enhancing the therapeutic effectiveness of substrate reduction therapy while reducing glycogen stores.
Solution Approach 2:
The patent modifies the chemical structure by varying the linker components (L1 and L2) and substituents (R1-R6, X1-X5, Q1) to optimize the compound's ability to inhibit GYS1. These parameter changes in molecular structure enhance the compound's binding affinity and selectivity, improving therapeutic effectiveness while reducing glycogen stores.
2Object-affected harmful factors
If GYS1 enzyme activity is inhibited to reduce glycogen accumulation, then disease progression is slowed, but selective inhibition of GYS1 over GYS2 is required to avoid off-target effects
Solution Approach 1:
The dimeric compound structure with specific linker configurations and substituent patterns enables selective binding to GYS1 enzyme while sparing GYS2. This local quality differentiation in molecular structure allows the compound to achieve selective inhibition, reducing glycogen accumulation without causing off-target effects on other glycogen synthase isoforms.
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 reduce glycogen stores, offering therapeutic benefits for patients with glycogen storage diseases and cancers by modulating GYS1 activity, potentially as a standalone treatment or in combination with existing therapies.
Implementation Method 1
Development of dimeric compounds that selectively inhibit glycogen synthase 1 (GYS1) enzyme activity, reducing tissue glycogen levels through glycogen substrate reduction therapy
Data Source
AI summary
Provided herein are compounds of formula (I): (G1-Z1)-L-(G2-Z2), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G1, G2, Z1, Z2, and L, are as defined elsewhere herein. Also provided herein are methods of preparing compounds of formula (I). Also provided herein are methods of inhibiting GYS1 and methods of treating a GYS1-mediated disease, disorder, or condition in an individual in need thereof.