P97 Modulators via Heterocyclic Scaffold Design
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Solution Overview
Problem
There is a need for effective inhibitors and modulators of the p97 protein to treat cancer and neurodegenerative disorders caused by proteostatic malfunction, with a requirement for compounds that are more efficacious and have fewer side effects than existing options.
Innovation Solution
Development of specific compounds with structures represented by formulas (I), (I′), and (II), which can modulate or inhibit p97 activity, thereby treating conditions such as inclusion body myopathy, Paget's disease of the bone, frontotemporal dementia, and amyotrophic lateral sclerosis, by administering these compounds to subjects in need, either orally or through other pharmaceutically acceptable methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing p97 inhibitors are used to treat cancer and neurodegenerative disorders, then therapeutic effect is achieved, but side effects occur and efficacy is insufficient
Solution Approach 1:
The patent modifies the chemical structure of p97 inhibitors by changing molecular parameters - specifically incorporating nitrogen-containing heterocyclic rings (pyridine, pyrimidine, triazine) at the 6-position of the core scaffold, and introducing specific functional groups (carboxylic acid, ester, amide) at the 3-position. These structural parameter changes result in compounds with improved binding affinity to p97 and selective modulation of its ATPase activity, achieving better therapeutic efficacy with reduced off-target effects and fewer side effects compared to prior art inhibitors.
2Reliability
If existing p97 inhibitors are used to treat cancer and neurodegenerative disorders, then therapeutic effect is achieved, but the compounds lack sufficient specificity and selectivity
Solution Approach 1:
The patent applies local quality by introducing specific functional groups at specific positions of the molecular scaffold. The 3-position carries carboxylic acid, ester, or amide groups that form specific interactions with p97 residues, while the 6-position contains nitrogen-containing heterocyclic rings that provide selective binding. This localized functionalization creates high specificity for p97 over other AAA ATPases, enabling selective modulation of p97 activity in cancer and neurodegenerative diseases without affecting related proteins.
3Stability of the object's composition
If p97 is inhibited to restore proteostasis in disease states, then cellular homeostasis is improved, but the mechanism of action is not fully understood and off-target effects occur
Solution Approach 1:
The patent compounds act as intermediary molecules that selectively bind to p97 and modulate its ATPase activity. The nitrogen-containing heterocyclic rings at the 6-position and carboxylic acid/ester/amide groups at the 3-position serve as mediating functional groups that interact with specific residues in the p97 active site. This intermediary binding mechanism allows precise control of p97 activity to restore proteostasis in disease states such as cancer and neurodegenerative disorders, while the well-defined binding mode reduces off-target effects and simplifies the mechanism of action compared to non-specific protein aggregation modifiers.
Data Source
AI summary
The present invention is directed to methods of inhibiting or modulating p97 and compounds and compositions useful in such methods. Diseases and conditions that can be treated with the compounds and compositions of the invention include, but are not limited to, cancer and neurodegenerative disorders susceptible to treatment by modulation or inhibition of p97.