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Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [Quant-seq]

ABSTRACT: Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [Quant-seq]

PROVIDER: PRJNA1304868 | ENA |

REPOSITORIES: ENA

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Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [Quant-seq]

Project description:TEAD proteins are a family of transcription factors that enable the oncogenic activity of deregulated Hippo signaling and are a promising therapeutic target in oncology. Targeting the lipid pocket of TEAD is an established path to inhibit the oncogenic activities of the cofactors YAP and TAZ. Here we present two covalent pan-TEAD inhibitors that bind to the lipid pocket, GNE-8025 and GNE-2181. GNE-8025 binds TEAD proteins covalently at a conserved cysteine residue to engage the lipid pocket and allosterically disrupt the interaction of TEAD proteins with YAP. GNE-2181 is a further optimized version of GNE-8025 with properties that enable brain penetrance in vivo. Both of these small molecules suppress the proliferation of YAP-driven tumor cells both in vitro and in vivo and increase activity of a broad range of inhibitors of the MAPK pathway. We demonstrate that these molecules have exceptional efficacy in Hippo-driven in vivo tumor models, including in a mouse model of brain metastases where GNE-2181 treatment significantly inhibits the growth of intracranial brain tumors. Altogether we present a next-generation class of TEAD inhibitors. The development of GNE-8025 and GNE-2181 is a significant advancement towards potent, specific, and effective Hippo-targeting cancer therapies.

2026-05-07 | GSE305227 | GEO

Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [RNA-seq]

2026-05-07 | GSE305224 | GEO

Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [ATAC-seq]

2026-05-07 | GSE330305 | GEO

Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models

Project description:Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models

| PRJNA1304927 | ENA

Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [RNA-seq]

Project description:Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [RNA-seq]

| PRJNA1304856 | ENA

Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [ATAC-seq]

Project description:Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models [ATAC-seq]

| PRJNA1463356 | ENA

Covalent pan-TEAD inhibitors block YAP activity and demonstrate brain penetrance in Hippo-dependent cancer models

Project description:This SuperSeries is composed of the SubSeries listed below.

2026-05-07 | GSE305254 | GEO

LiP-Quant, an automated chemoproteomic approach to identify drug targets in complex proteomes

Project description:Chemoproteomics is a key technology to characterize the mode of action of drugs, as it directly identifies the protein targets of bioactive compounds and aids in developing optimized leads. We have developed a drug target deconvolution approach with an automated data analysis pipeline, based on limited proteolysis coupled with mass spectrometry that works across species including in human cells (LiP-Quant). Here we demonstrate drug target identification by LiP-Quant across compound classes, including with drugs targeting kinases and phosphatases . We demonstrate that LiP-Quant identifies drug binding sites, a unique feature of this approach, and that it can be used to estimate drug EC50s in whole cell lysates . LiP-Quant identifies targets of both selective and promiscuous drugs and correctly discriminates drug binding to homologous proteins. We finally show that the LiP-Quant technology identifies targets of a novel research compound of biotechnological interest.

2020-09-09 | PXD015446 | Pride

LiP-Quant, an automated chemoproteomic approach to identify drug targets in complex proteomes, p2

2020-09-09 | PXD018204 | Pride

Lysine long-chain fatty acylation regulates the TEAD transcription factor

Project description:TEAD transcription factors are responsible for the transcriptional output of Hippo signalling1,2. TEAD activity is primarily regulated by phosphorylation of its coactivators YAP and TAZ3,4. In addition, cysteine palmitoylation has recently been shown to regulate TEAD activity5,6. Here, we report lysine long-chain fatty acylation as a novel posttranslational modification of TEADs. Lysine fatty acylation occurs spontaneously via intramolecular transfer of acyl groups from the proximal acylated cysteine residue. Lysine fatty acylation, like cysteine palmitoylation, contributes to the transcriptional activity of TEADs by enhancing the interaction with YAP and TAZ, but it is more stable than cysteine acylation, suggesting that the lysine fatty-acylated TEAD acts as a “stable active form”. Significantly, lysine fatty acylation of TEAD increased upon Hippo signalling activation, despite a decrease in cysteine acylation. Our results provide new insight into the role of fatty acyl modifications in the regulation of TEAD activity.

2023-03-19 | PXD033939 | Pride

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