Selective GYS1 Inhibitors for Pathological 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 tissue glycogen levels and improve patient outcomes.
Innovation Solution
Development of compounds that inhibit glycogen synthase 1 (GYS1) enzyme activity to reduce tissue glycogen stores, potentially used alone or in combination with existing therapies like enzyme replacement therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glycogen synthase activity is inhibited to reduce tissue glycogen stores, then therapeutic benefit is achieved in diseases of glycogen storage, but enzyme activity is suppressed which may affect normal glycogen metabolism
Solution Approach 1:
The patent applies local quality by designing inhibitors with selective affinity for the GYS1 isoform over GYS2, achieving tissue-specific inhibition in muscles and liver where GYS1 is predominantly expressed. This selectivity allows therapeutic reduction of pathological glycogen accumulation while preserving normal glycogen metabolism in other tissues through isoform-specific targeting
Solution Approach 2:
The patent employs partial action by developing inhibitors that partially suppress GYS1 activity rather than completely blocking it. This partial inhibition is sufficient to reduce pathological glycogen stores in diseases like Pompe disease and cancer, while avoiding complete suppression that would disrupt essential glycogen metabolism required for normal cellular function
2Reliability
If substrate reduction therapy is used to treat glycogen storage diseases, then glycogen accumulation is reduced, but treatment options are limited compared to other storage disorders
Solution Approach 1:
The patent achieves universality by developing GYS1 inhibitors with broad applicability across multiple glycogen storage diseases including Pompe disease, Cori disease, adult polyglucosan body disease, Lafora disease, and certain cancers. A single inhibitor class can address diverse pathological conditions caused by abnormal glycogen accumulation, providing a versatile therapeutic platform that extends beyond disease-specific treatments
3Quantity of substance
If glycogen synthase is inhibited to reduce cellular glycogen stores, then energy dense storage is reduced, but cellular energy availability may be impacted
Solution Approach 1:
The patent applies partial action by implementing moderate inhibition of GYS1 that reduces pathological glycogen accumulation to therapeutic levels while maintaining sufficient glycogen stores for normal cellular energy needs. The inhibition is calibrated to achieve disease modification without complete depletion of energy reserves
Solution Approach 2:
The patent uses local quality by targeting GYS1 inhibition specifically in tissues with pathological glycogen accumulation (such as muscles in Pompe disease or tumor cells in cancer), while preserving normal glycogen metabolism in healthy tissues. This spatially selective approach ensures energy availability is maintained in non-affected tissues
Data Source
AI summary
Provided herein are compounds of formula (I′):or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y2, Y3, L1, L2, X1, X2, X3, X4, X5, Q1, R1, R2, Rk, Rm, and Rn 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.