VT104

Protein target name:

TEAD1, TEAD2, TEAD3, TEAD4

Mechanism of action:

Inhibitor

Recommended Concentration for use in cells:

up to 3 uM

Probe Availability

MedKoo Biosciences, Inc.

Probe Information

Target and Probe Information

Target Details

Target class:

Transcription factor

Subclass:

TEA Domain

HUGO ID:

HGNC:11714 HGNC:11715 HGNC:11716 HGNC:11717

Entrez gene ID:

7003 8463 7005 7004

UNIPROT ID:

P28347 Q15562 Q99594 Q15561

Target alias:

AA; REF1; TCF13; TEF-1; NTEF-1; TCF-13; TEAD-1;ETF; TEF4; TEF-4; TEAD-2; TEF5; TEAD5; TEF-5; DTEF-1; ETFR-1; TEAD-3; TEF3; RTEF1; TEF-3; EFTR-2; TEFR-1; TCF13L1; hRTEF-1B

Probe Details

Chemical Probes Portal ID:

CPP2363

Probe alias:

cpd 89

PubChem CID:

146909371

SMILES string:

FC(F)(F)C(C=C1)=CC=C1C2=CC=CC3=CC(C(N[C@@H](C)C4=NC=CC=C4)=O)=CC=C23

InChi Key:

AAZUPSFRSHFTGV-INIZCTEOSA-N

Control compound:

VT106

Orthogonal probe:

VT103

Physico-chemical properties

NMR:

1H NMR (400 MHz, DMSO-r/e) d 8.56 (d, 7 = 1.5 Hz, 1H), 8.46 (d, 7 = 8.1 Hz, 1H), 8.13 (d, 7 = 8.3 Hz, 1H), 7.96 - 7.90 (m, 3H), 7.81 (d, J= 8.9 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.69 (d, J= 8.1 Hz, 1H), 7.60 (dd, J= 0.9, 7.1 Hz, 1H), 4.27 (spt, J= 6.9 Hz, 1H), 3.49 - 3.42 (m, 1H), 3.35 (br s, 1H), 3.30 (s, 3H), 1.19 (d, 7 = 6.8 Hz, 3H).

Validation in Cells and Model Organisms

In vitro validation

On target activity

Potency:

ΔTm

8.6 TEAD1, 5.4 TEAD2, 8.2 TEAD3, 4.3 TEAD4

Potency assay:

Thermal Shift Assays (TSA), Cell-free TEAD palmitoylation assay

PDB ID for probe-target interaction (3D structure):

7CNL

Structure-activity relationship:

yes

In cell validation

On target activity in cells

Potency in cells:

IC50, GI50

10.4 ± 0.8 nM (Y), 16-98 nM (C)

Potency assay (cells):

YAP reporter assay (Y), Cell proliferation assay (C), Cell-based TEAD palmitoylation assays (APEGS Assay)

Off target activity in cells

Potency in cells, off target:

GI50

Potency assay, off target (cells):

Anti-proliferation activity in a panel of mesothelioma cell lines

Probe Selectivity in Cell:

GI50 (nM) NCI-H226 16, NCI-H2373 26, Mero-48a 98, SDM103T2 60, NCI-H2052 33, ACC-MESO-1 20, ZL34 46, JU77 70, Mero-95 303, ZL55 101, ZL5 236, Mero-82 243, ONE58 135, Mero-14 124, Mero-83 214, Mero-41 984, SPC111 1945, SPC212 >3000, NO36 >3000, Mero-84 >3000, ACC-MESO-4 1098, Mero-25 >3000, NCI-H28 >3000, NCI-H2452 >3000, MSTO-211H >3000, HMMME >3000

In vivo validation

Organism:

Mouse

Dose:

10 mg/Kg

Route of delivery:

OralIntravenous

Plasma half life:

24.2 h (IV)

Systemic clearance:

1.8 mL/min/kg (IV)

Cmax:

2,160 ng/mL (PO)

Tmax:

4 h (PO)

Vss:

3.6 L/Kg (IV)

AUC:

49.0 (IV), 38.4 (PO) μg*h/mL

Bioavailability:

78 %

Primary Reference

Reference (doi):

10.1158/1535-7163.MCT-20-0717

Reference (PMID):

33850002

Under Review

This probe is in the process of SAB review. Please continue to check back for new reviews and commentary.

SAB Rating

Rating for use in Cells

2 review(s)

Rating for use in Model Organisms

2 review(s)

SAB Members

SAB Comments

The Hippo pathway governs organ size and tissue homeostasis, regulating several fundamental cellular processes such as cell proliferation, migration, apoptosis and cell-fate decision. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are its main two-terminal effectors, mediating most of its physiological functions. When the Hippo upstream pathway inhibition promotes YAP/TAZ translocation to the nucleus, where they form the active complex with the transcriptional-enhancer-associate-domain (TEAD) family of transcription factors to control the expression of target genes. YAP and TAZ activity is key in the amplification of tissue-specific progenitor cells during tissue renewal and regeneration, and cell proliferation. In tumours, they play an important role in cancer development, progression and metastasis. As such, they are attractive targets for cancer therapy and for regenerative medicine applications. In particular, regulating the complex formation/interactions of YAP/TAZ with TEAD, and subsequent target gene activation has been reported as a valuable strategy. The small-molecule VT104 is a potent and selective TEAD inhibitor that blocks TEAD auto-palmitoylation, and thus disrupt the interaction with YAP/TAZ. In particular, this is a pan-TEAD palmitoylation inhibitor, that inhibits all four TEAD 1-4 proteins by binding directly to TEAD in the central lipid pocket. VIT104 shows strong antitumor efficacy in the human mesothelioma NCI-H226 CDX model. The compound has been identified through a comprehensive set of cellular, biochemical, biophysical and structural studies and in vivo investigation.

Sep 21 2021 - 10:48am

VT104

Probe Availability

Probe Information

Target Details

AA; REF1; TCF13; TEF-1; NTEF-1; TCF-13; TEAD-1;ETF; TEF4; TEF-4; TEAD-2; TEF5; TEAD5; TEF-5; DTEF-1; ETFR-1; TEAD-3; TEF3; RTEF1; TEF-3; EFTR-2; TEFR-1; TCF13L1; hRTEF-1B

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

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VT104

Probe Availability

Probe Information

Target Details

AA; REF1; TCF13; TEF-1; NTEF-1; TCF-13; TEAD-1;ETF; TEF4; TEF-4; TEAD-2; TEF5; TEAD5; TEF-5; DTEF-1; ETFR-1; TEAD-3; TEF3; RTEF1; TEF-3; EFTR-2; TEFR-1; TCF13L1; hRTEF-1B

Probe Details

Physico-chemical properties

In vitro validation

In cell validation

In vivo validation

Primary Reference

Supporting Organizations

Interested in supporting the portal?