YAP/TEAD Modulator Compounds for Selective Hippo Pathway Inhibition
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Solution Overview
Problem
There is an unmet need for effective YAP/TEAD inhibitors to modulate the interaction between YAP and TEAD proteins, which are involved in the Hippo signaling pathway, as current treatments for diseases associated with this pathway are lacking.
Innovation Solution
Development of novel compounds, as described in Formula (I), and their pharmaceutical compositions that can modulate the YAP/TEAD interaction, potentially inhibiting their binding to reduce the expression of target genes and exhibit anti-proliferative effects in cancer cell lines.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If no YAP/TEAD inhibitors are available, then there is no therapeutic option for diseases mediated by Hippo pathway deregulation, but developing new compounds requires significant research investment and time
Solution Approach 1:
The patent performs preliminary actions by conducting extensive in silico screenings, in vitro assays, and in vivo studies before clinical application. Multiple compounds (Formula I, II, III) were pre-developed and characterized with known mechanisms of YAP/TEAD inhibition, reducing the time needed for therapeutic development and providing ready-to-use treatments for Hippo pathway-mediated diseases.
2Reliability
If Verteporfin is used to inhibit YAP/TEAD interaction, then some therapeutic effect is achieved, but the compound has limitations in efficacy and selectivity
Solution Approach 1:
The patent applies parameter changes by modifying chemical structures (Formula I, II, III with various R1-R6 substituents) to optimize binding affinity and selectivity. The compounds feature diverse chemical moieties including heterocyclic rings, aromatic groups, and specific functional groups that enhance YAP/TEAD inhibition efficacy while improving selectivity over other protein interactions, overcoming Verteporfin's limitations.
3Productivity
If YAP/TEAD inhibitors are developed to reduce target gene expression, then anti-proliferative effects are achieved in cancer cell lines, but the compounds may affect other cellular processes
Solution Approach 1:
The patent uses the YAP/TEAD protein complex as a specific intermediary target. The compounds (Formula I, II, III) are designed to bind specifically to this complex, which acts as an intermediary between upstream Hippo pathway signals and downstream transcriptional programs. By targeting this specific intermediary rather than affecting all cellular processes, the compounds achieve anti-proliferative effects while minimizing off-target toxicity.
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 R1, R2, R3, R4, L and X are as described in any of the embodiments described in this disclosure; compositions thereof, and uses thereof.