P1/2, N=434, Recruiting, Vivace Therapeutics, Inc | Trial completion date: Jun 2027 --> Mar 2030 | Trial primary completion date: Dec 2026 --> Nov 2029

Dysfunction of Hippo signaling resulting in elevated YAP/TAZ-TEAD activity is commonly associated with tumorigenesis and represents a therapeutic target for cancer...Importantly, the pan-TEAD inhibitors also promote synergistic cell death in EGFR- and KRAS mutant Non-Small Cell Lung Cancer (NSCLC) cells, which may eventually overcome drug resistance associated with the use of FDA-approved compounds. Therefore, we uncover a novel class of vinyl sulfone warhead-bearing pan-TEAD inhibitors with potential for treating gastric and mutant KRAS and EGFR lung cancers.

It explores the crosstalk between Hippo-YAP/TAZ signalling and other oncogenic pathways, including Wnt/β-catenin and PI3K/Akt, as well as the influence of tumour microenvironmental factors such as hypoxia and extracellular matrix stiffness on pathway activation. Additionally, emerging therapeutic strategies targeting YAP/TAZ-TEAD interactions and upstream regulators are discussed, offering potential avenues for improving gastric cancer outcomes in diagnosis and treatment.

In this study, we investigated the anti-inflammatory and anti-invasive properties of 1,3,6-tri-O-galloyl-α-D-glucose (αTGG), the α-anomer of βTGG from Terminalia chebula, in comparison with pharmacological Hippo pathway inhibitors IAG933, VT107, and GNE7883...Importantly, αTGG and VT107 also significantly attenuated ConA-induced activation of proMMP-2 to MMP-2 and reduced the expression of multiple pro-inflammatory mediators, including COX2, CCL22, CCR2, CCR4, CXCL10, CXCL12, CXCR1, FASLG, IFNG, IL13, and IL17A. These findings underscore the dual anti-inflammatory and anti-invasive actions of αTGG, positioning it as a promising candidate for targeting inflammation-driven GBM progression through modulation of Hippo pathway activity.

P1/2, N=219, Not yet recruiting, TYK Medicines, Inc

The patient was treated with VT3989, a YAP/TEAD inhibitor, for 5 cycles...Downregulation of the Hippo signaling pathway via YAP/TEAD inhibition in an adult patient may result in a phenotype resembling a mild form of HPCD (Sveinsson chorioretinal atrophy), underscoring the importance of this pathway in maintenance of the adult retina and retinal pigment epithelium. As novel cancer therapeutics continue to emerge, it may be important to ensure ophthalmologic monitoring of patients on drugs targeting the Hippo pathway.

These findings, and tumor cell growth suppression were confirmed in NF2 fl/fl;Peri-Cre mouse model 7 , and in human derived schwannoma cells treated with a pan-TEAD auto palmitoylation inhibitor VT3989. 8 Our computational and experimental results confirm that TEAD1 inhibition could be a potent, targeted strategy for schwannomas.

P1, N=137, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

They demonstrated efficacy against colorectal cancer cells resistant to the KRAS-dependent clinical candidate IAG933 and confirmed the ability to inhibit TEAD4 target genes expression. Bioinformatic metabolic pathway analysis further differentiated the mechanism of action of the 6a analogs from verteporfin, a known indirect modulator of the Y:T complex. These findings establish the pyrazolo-piperidinone class as novel Y:T disruptors and provide insights into their metabolic impact on downstream effectors, offering a valuable framework for future hit-to-lead optimization and mechanism of action studies.

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.

P1/2, N=336, Recruiting, Vivace Therapeutics, Inc | Phase classification: P1 --> P1/2

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.