Undisclosed YAP/TAZ-TEAD inhibitor

Here, we develop a high-content pipeline that enables a comparative analysis of currently developed YAP/TAZ-TEAD inhibitors...We identify genetic compensation of the Hippo pathway transcriptional module, with implications for therapeutic targeting, and implement Cell Painting to develop a detailed morphological profiling pipeline that enables further characterisation, quantification, and analysis of off-target effects. Our pipeline is scalable and allows us to establish specificity and comparative potency within cancer-relevant assays in a clinically relevant cellular model of pleural mesothelioma.

Current therapeutic innovation focuses on molecular diagnostics and precision targeting approaches, including direct YAP/TAZ-TEAD complex inhibitors, upstream receptor modulators, and rational combinations with immune checkpoint blockade. Future investigations should employ multi-omics profiling to delineate tumor subtype-specific regulatory architectures while advancing novel drug delivery platforms. These efforts promise to translate mechanistic insights into multi-targeted therapeutic strategies capable of overcoming resistance mechanisms and improving survival outcomes for this therapeutically challenging malignancy.

Pharmacological inhibition of YAP/TAZ-TEAD interaction by Verteporfin significantly decreased tumor cell growth, whereas specific inhibition of TEAD3 did not impact cell proliferation but affected sterol/cholesterol biosynthetic and metabolic processes. This study contributes to a better understanding of the role of Hippo effectors in glioblastoma pathophysiology. These transcription factors, particularly TEAD3, could potentially serve as therapeutic targets, especially considering recent data on cholesterol homeostasis in glioblastomas.

Our findings establish the cardiac glycoside PPM as a novel ferroptosis sensitizer that targets ATP1A1 to activate the Src-YAP/TAZ-TFRC axis, providing mechanistic insights for repurposing cardiac glycosides as ferroptosis modulators in precision combinatorial cancer therapy.

We further show that inhibition of the YAP/TAZ-associated TEAD family of transcription factors blocks the development of the carcinomas and associated microenvironment. These observations demonstrate that carcinomas resulting from Hippo pathway dysregulation in the mammary epithelium are sufficient to drive cellular events that promote a basal-like tumor-associated niche and suggest that targeting dysregulated YAP/TAZ-TEAD activity may offer a therapeutic opportunity for basal-like mammary tumors.

Higher levels of downstream Hippo effectors are associated with poor response to platinum-pemetrexed doublet and worse OS. The stratification of ePM based on the activation of the YAP/TAZ-TEAD axis is an intriguing approach in the light of the inhibitors of this signaling that are currently under investigation.

And disordered Hippo pathway and YAP/TAZ-TEAD activity are related to tumor progression...The study clarify a novel miR-424-5p/TXNIP/Hippo signaling pathway that facilitated CRC cells proliferation, migration and invasion. The above findings suggested that miR-424-5p and TXNIP might serve as the potential therapeutic targets for CRC patients.

Here, we provide the pre-clinical evidence for the antitumor activity of novel smTEADi, SW-682 in HPV-negative HNSCC. A HNSCC-specific TEADi target gene set was defined from RNA-seq data, which is highly expressed in HNSCC tissues and predicts poor prognosis of HPV-negative HNSCC patients. Our results underscore that YAP/TAZ-TEAD-mediated growth-promoting programs represent a vulnerability in HPV-negative HNSCC, thus providing a pre-clinical rationale for the future evaluation of YAP/TAZ-TEAD targeting strategies as a therapeutic approach for HPV-negative HNSCC patients.

YAP/TAZ-TEAD facilitates the upregulation of multiple genes involved in evolutionary cell proliferation and survival...Subsequently, we optimized several analogs of BC-001 and found that the optimized compound BC-011 exhibited an IC50 of 72.43 nM. These findings can be used to design effective TEAD modulators with anticancer therapeutic implications.

Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors...More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

Inhibiting YAP pathway either by addition of verteporfin, an inhibitor of YAP/TAZ-TEAD, or by transfection of si-RNAs targeting YAP or TAZ further enhances silibinin-induced cell damage. While enhancing YAP activity by silencing LATS1/2 or overexpressing YAPS127/397A, an active form of YAP, attenuates silibinin-induced cell damage. These findings demonstrate that inhibition of the YAP/TAZ pathway contributes to cytotoxicity of silibinin in breast cancers, shedding lights on YAP/TAZ-targeted cancer therapies.

Given the limited effectiveness of current treatments, targeting the YAP/TAZ-TEAD signalling cascade has emerged as a promising therapeutic strategy in MPM. Several inhibitors of the YAP/TAZ-TEAD signalling axis are presently undergoing clinical development, with the goal of advancing them to clinical use in the near future.