PKM2 Activators Locking Enzyme in Active Conformation
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Solution Overview
Problem
Current treatments for diseases such as cancer, diabetes, obesity, autoimmune conditions, and benign prostatic hyperplasia related to pyruvate kinase function lack selectivity, particularly in targeting the PKM2 isoform, which is exclusively expressed in tumor cells and plays a crucial role in glycolysis and biosynthesis.
Innovation Solution
Development of specific compounds that activate PKM2 by binding to it, locking the enzyme in an active conformation and preventing allosteric control, thereby inhibiting the growth and proliferation of cancer cells, immune cells, and fat cells, while modulating glycolysis and biosynthesis pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current pyruvate kinase inhibitors are used, then pyruvate kinase function is inhibited, but the treatment lacks selectivity for PKM2 isoform, making it difficult to treat diseases related to PKM2 function
Solution Approach 1:
The patent applies local quality by designing compounds that specifically target the PKM2 isoform's unique allosteric activation mechanism. The compounds interact with the FBP binding site on PKM2, exploiting the isoform-specific dependence on FBP activation to achieve selective inhibition of PKM2 while sparing other PKM1 and PKM2 forms in normal tissues.
Solution Approach 2:
Instead of using conventional competitive inhibitors that bind to the active site, the patent inverts the approach by using allosteric modulators that bind to the FBP binding site. This inversion allows selective targeting of PKM2's unique regulatory mechanism, achieving isoform-specific control over PKM2 activity.
2Reliability
If PKM2 is activated to treat cancer, then cancer cell growth is inhibited, but the compounds must be highly specific to avoid affecting normal cells with PKM2 expression
Solution Approach 1:
The patent achieves local quality by targeting the specific allosteric activation mechanism of PKM2 through FBP analogs. This approach exploits the unique regulatory property of PKM2 (dependence on FBP activation) to selectively modulate its activity in cancer cells while minimizing effects on normal cells that express PKM1 or constitutively active PKM2.
Solution Approach 2:
The patent applies parameter changes by modifying the FBP molecule to create analogs with altered binding characteristics. These modifications enable the compounds to selectively bind to PKM2's allosteric site, changing the activation parameter specifically for PKM2 without affecting other PK isoforms or normal cellular processes.
3Ease of operation
If phosphotyrosine peptide binds to PKM2, then FBP dissociates and conformational changes occur, but this leads to loss of allosteric control needed for shunting biochemical intermediates
Solution Approach 1:
The patent uses FBP analogs as intermediary compounds that bind to the allosteric site on PKM2. These intermediaries prevent the dissociation of FBP and maintain the active tetrameric conformation of PKM2, thereby preserving allosteric control and preventing the harmful conformational change to the inactive form.
Solution Approach 2:
The patent applies preliminary anti-action by pre-binding FBP analogs to the allosteric site on PKM2 before phosphotyrosine peptide binding can occur. This preliminary binding prevents the conformational change and maintains PKM2 in its active state, counteracting the harmful effect of phosphotyrosine peptide-induced inactivation.
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 activate PKM2, enhancing lactate production or oxidative phosphorylation, providing a therapeutic benefit by selectively targeting cancer and other conditions related to reduced PKM2 activity with increased specificity and efficacy.
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
Cancer cells rely primarily on glycolysis to generate cellular energy and biochemical intermediates for biosynthesis of lipids and nucleotides
Implementation Method 3
enhancing lactate production or oxidative phosphorylation
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.