Phosphorus-Containing Compounds for Electrostatic TEAD Binding
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Solution Overview
Problem
Current treatments for cancers involving the YAP/TAZ-TEAD protein complex are limited by the lack of small molecules that can effectively bind to the electrostatically enriched pockets in the TEAD protein, and inhibiting palmitoylation of TEAD family proteins is challenging due to the geometrically characterized interfaces.
Innovation Solution
Development of phosphorus-containing compounds that inhibit the transcriptional activity of the YAP/TAZ-TEAD protein complex, offering improved physicochemical and pharmacokinetic properties, reduced toxicity, and enhanced safety profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecules are designed to bind to electrostatically enriched pockets in TEAD protein, then binding affinity may be improved, but the geometrically characterized interfaces lack suitable pockets for small molecule binding
Solution Approach 1:
The patent introduces phosphorus-containing compounds with specific molecular parameters (phosphine oxide or phosphinate groups) to change the binding characteristics. These compounds have molecular weights of 300-800 Da and contain polar phosphorus groups that can interact with the electrostatically enriched pockets of TEAD protein, resolving the contradiction between binding affinity and structural complexity by optimizing molecular parameters
Solution Approach 2:
The patent designs compounds where the phosphorus-containing functional groups are positioned at specific locations within the molecular structure to target specific electrostatically enriched pockets in the TEAD protein. This local quality approach allows the molecule to have complex features only where needed for binding, while maintaining simplicity in other regions
2Reliability
If phosphorus-containing compounds are developed to inhibit YAP/TAZ-TEAD complex, then therapeutic efficacy is improved, but synthesis complexity and manufacturing difficulty increase
Solution Approach 1:
The patent divides the phosphorus-containing compound into modular segments: a core structure and phosphorus-containing functional groups (phosphine oxide or phosphinate). This segmentation allows for systematic synthesis where the core structure can be prepared separately and then coupled with the phosphorus-containing moieties, reducing overall synthesis complexity while maintaining therapeutic efficacy
Solution Approach 2:
The patent employs linkers as intermediary components connecting the core structure to the phosphorus-containing functional groups. These linkers serve as modular building blocks that facilitate stepwise synthesis and allow for optimization of both efficacy and manufacturability by enabling standardized coupling reactions
3Reliability
If compounds are designed with improved bioavailability and metabolic stability, then pharmacokinetic properties are enhanced, but molecular structure complexity increases
Solution Approach 1:
The patent optimizes pharmacokinetic properties by controlling molecular weight (300-800 Da) and introducing phosphorus-containing groups with specific parameters. These parameter changes improve bioavailability and metabolic stability while keeping the molecular structure within manageable complexity limits through systematic optimization
Data Source
AI summary
Provided in the present invention are a phosphorus-containing compound, a pharmaceutical composition and the use thereof. Specifically, provided are a compound as represented by formula I, a pharmaceutically acceptable salt, an ester, a stereoisomer, a tautomer, a polymorph, a solvate, a metabolite, an isotopic derivative or a prodrug thereof. The phosphorus-containing compound of the present invention can effectively treat diseases and conditions mediated by TEAD, such as cancer.