PKM2-Modulating Therapeutic Compounds for Isoform Selectivity
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Solution Overview
Problem
Current inhibitors of pyruvate kinase are not selective, making it difficult to treat diseases related to pyruvate kinase function, such as cancer, diabetes, obesity, autoimmune conditions, and proliferation-dependent diseases like benign prostatic hyperplasia, as all tumor cells exclusively express the embryonic M2 isoform of pyruvate kinase (PKM2).
Innovation Solution
Development of compounds that modulate pyruvate kinase M2 (PKM2), including activating compounds that bind to PKM2 and lock the enzyme in an active confirmation, thereby inhibiting the growth and proliferation of cancer cells, activated immune cells, and fat cells, while diverting glucose metabolites into catabolic processes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current inhibitors of pyruvate kinase are used, then pyruvate kinase activity is inhibited, but the inhibitors lack selectivity and cannot distinguish between different PK isoforms
Solution Approach 1:
The patent applies local quality by designing inhibitors that specifically target the unique structural features of PKM2 isoform. The compounds are engineered to recognize and bind selectively to PKM2's distinct active site configuration and allosteric regulatory regions, which differ from PKM1 and other isoforms. This selective binding achieves high isoform-specific inhibition without affecting other PK variants, resolving the selectivity problem through localized molecular recognition.
Solution Approach 2:
The patent employs parameter changes by modifying chemical structures to optimize binding affinity and selectivity for PKM2. The invention involves systematically varying molecular parameters such as substituent groups, ring structures, and stereochemistry to enhance discrimination between PK isoforms. These parameter optimizations enable the inhibitors to achieve selective binding to PKM2 while maintaining appropriate pharmacokinetic properties.
2Reliability
If PKM2 is inhibited to treat cancer, then cancer cell proliferation is reduced, but normal cells expressing PKM2 (adipose tissue, activated T-cells) are also affected
Solution Approach 1:
The patent applies partial action by designing inhibitors with selective potency profiles. The compounds are engineered to inhibit PKM2 at therapeutic concentrations while exhibiting significantly reduced activity against PKM1 and other isoforms. This selective potency allows the inhibitors to achieve anti-cancer efficacy by targeting tumor cells that heavily rely on PKM2, while sparing normal tissues where PKM1 predominates or where PKM2 expression is lower.
Solution Approach 2:
The patent employs intermediary mechanisms by utilizing the unique allosteric regulatory properties of PKM2 as a selective target. The inhibitors are designed to exploit PKM2's distinctive conformational states and allosteric sites that are not present or are structurally different in other isoforms. This intermediary approach uses PKM2's unique biochemical characteristics as a molecular handle for selective inhibition, thereby achieving therapeutic efficacy with reduced off-target effects.
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 modulate PKM2 activity, inhibiting cell proliferation and treating diseases associated with PKM2 function by maintaining the enzyme in an active conformation, thus providing therapeutic benefits for conditions like cancer, diabetes, obesity, and autoimmune disorders.
Implementation Method 1
M2 is a low-activity enzyme that relies on allosteric activation by the upstream glycolytic intermediate, fructose-1,6-bisphosphate (FBP)
Implementation Method 2
phosphotyrosine peptide binding to PKM2 leads to a dissociation of FBP from PKM2 and conformational changes of PKM2 from an active, tetrameric form to an inactive form
Data Source
AI summary
Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.