YAP/TEAD Modulator Compounds for Anti-Proliferative Therapy
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Solution Overview
Problem
There is an unmet need for compounds that can modulate the interaction between YAP and TEAD proteins to treat diseases associated with the Hippo signaling pathway, particularly in cancers, as current YAP/TEAD inhibitors are not approved for human treatment.
Innovation Solution
Development of novel organic compounds, including pharmaceutically acceptable salts, tautomers, stereoisomers, and deuterated analogs, which can modulate the YAP/TEAD interaction, thereby reducing the expression of target genes and displaying anti-proliferative effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Verteporfin is used to target the Hippo signaling pathway, then YAP/TEAD interaction is inhibited, but the compound is not approved for human treatment and lacks sufficient therapeutic efficacy
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of Verteporfin through substitution at specific positions (R1-R6, R12-R13) with various functional groups including halogens, alkyl groups, aryl groups, and heteroaryl groups. These structural parameter changes aim to optimize the compound's binding affinity to YAP/TEAD, improve therapeutic efficacy, and achieve approval for human treatment while maintaining the core mechanism of inhibiting YAP/TEAD interaction
Solution Approach 2:
The patent employs composite material principles by creating hybrid molecular structures that combine the core Verteporfin scaffold with diverse substituent groups. The compounds integrate multiple functional moieties (e.g., fluorinated groups, methyl groups, heterocyclic rings) into a single molecular entity, resulting in composite structures with enhanced pharmacological properties and improved suitability for human therapeutic applications
2Reliability
If YAP/TEAD inhibitors are developed to reduce expression of target genes, then anti-proliferative effects are achieved, but no compounds are currently approved for treatment or prevention of diseases in humans
Solution Approach 1:
The patent systematically varies chemical parameters including substitution patterns, molecular weight, lipophilicity, and steric properties to optimize the balance between anti-proliferative efficacy and safety profile. By adjusting these parameters across multiple compounds in the series, the invention aims to identify candidates with sufficient therapeutic index for human approval while maintaining potent YAP/TEAD inhibition
Solution Approach 2:
The patent uses the compounds as intermediary agents that mediate between the Hippo signaling pathway and disease outcomes. These small molecule intermediaries bind to YAP/TEAD complex, preventing transcriptional activation of pro-growth genes, thereby serving as therapeutic intermediaries that translate molecular inhibition into clinical benefit for approved disease treatments
3Reliability
If compounds are designed to modulate YAP/TEAD interaction, then tumor growth is inhibited, but the structural complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the molecular structure into distinct functional domains: a core Verteporfin scaffold responsible for YAP/TEAD binding, and substituent groups at specific positions (R1-R6, R12-R13) that fine-tune activity and selectivity. This modular segmentation allows systematic optimization of tumor growth inhibition while managing structural complexity through defined substitution patterns
Solution Approach 2:
The patent achieves universality by designing a core scaffold that maintains consistent YAP/TEAD binding capability across all compounds, while substituents provide additional functions such as improved solubility, metabolic stability, and selective targeting. This multi-functional design enables a single compound series to address multiple aspects of tumor growth inhibition without proportionally increasing overall structural complexity
Data Source
AI summary
Disclosed are compounds of Formula (I):or a pharmaceutically acceptable salt, a tautomer, a stereoisomer, or a deuterated analog thereof, wherein ring A, ring B, G, R2, R3, R4, Cx, p, q, v, X, and Z are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.