Tetrahydropyridopyrimidine TEAD Inhibitors With Lower Toxicity
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Solution Overview
Problem
There is a need for novel therapeutics with improved potency, reduced side-effects, lower toxicity, and better pharmacokinetic properties to inhibit YAP/TAZ-TEAD activation, which drives tumorigenesis and fibrosis, and is often associated with cancer and fibrotic diseases.
Innovation Solution
Development of novel compounds that inhibit YAP/TAZ-TEAD transcription, offering potential treatments for a wide range of cancers and fibrotic disorders by targeting the YAP/TAZ-TEAD protein-protein interaction.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing YAP/TAZ-TEAD inhibitors are used, then YAP/TAZ-TEAD transcription is inhibited, but potency is insufficient and side effects are high
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structure parameters of the inhibitor compounds. This includes varying substituents at specific positions (R1-R6 groups), changing molecular weight, lipophilicity, and other physicochemical properties to optimize the balance between inhibition potency and reduced toxicity. The structure-activity relationship studies guide these parameter changes to achieve better therapeutic windows.
Solution Approach 2:
The patent applies local quality by introducing specific functional groups and substituents at particular positions within the molecular structure. Different regions of the molecule are optimized independently - for example, certain substituents enhance binding affinity to the TEAD pocket while other regions are designed to improve pharmacokinetic properties and reduce off-target effects, creating localized functional optimizations throughout the molecule.
2Reliability
If YAP/TAZ-TEAD transcription is strongly inhibited, then tumorigenesis and fibrosis are suppressed, but therapeutic window narrows due to increased toxicity
Solution Approach 1:
The patent employs intermediaries in the form of carefully designed molecular linkers and spacer groups that mediate between the pharmacophore core and peripheral substituents. These intermediary elements allow the active portion of the molecule to effectively inhibit YAP/TAZ-TEAD while the intermediary structures modulate drug metabolism, reduce reactive metabolite formation, and improve overall safety profile, thus expanding the therapeutic window.
3Reliability
If novel compounds are developed with improved properties, then potency and safety are enhanced, but development complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the inhibitor molecule into distinct functional modules or building blocks (core structure, substituent groups R1-R6, linker elements). This modular approach allows independent optimization of each segment for specific properties (binding affinity, metabolic stability, solubility) while simplifying the overall development process through systematic combination of pre-validated building blocks with known properties.
Data Source
AI summary
The present disclosure relates to novel compounds, to said compounds for use as a medicine, more in particular for the prevention or treatment of diseases mediated by activity of YAP/TAZ-TEAD transcription, yet more in particular for the prevention or treatment of cancer or fibrosis. The present disclosure also relates to a method for the prevention or treatment of said diseases comprising the use of the novel compounds. The present disclosure furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds as well as to said compositions or preparations for use as a medicine, more preferably for the prevention or treatment of diseases mediated by activity of YAP/TAZ-TEAD transcription, yet more in particular for the prevention or treatment of cancer or fibrosis. The present disclosure also relates to processes for the preparation of said compounds.