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Purity: ≥98%
VT-103 (VT103) is an oral and potent TEAD1 protein Auto-palmitoylation inhibitor with anticancer activity. It inhibits YAP/TAZ-TEAD promoted gene transcription, blocks TEAD auto-palmitoylation, and disrupts interaction between YAP/TAZ and TEAD.VT-103 exhibited excellent oral bioavailability and pharmacokinetics with the ability to selectively inhibit NF2-deficient mesothelioma cell proliferation in vitro and growth of subcutaneous tumor xenografts in vivo. These highly potent and selective TEAD inhibitors provide a way to target the Hippo-YAP pathway, which thus far has been undruggable and is dysregulated frequently in malignant mesothelioma and in other YAP-driven cancers and diseases.
| Targets |
TEAD1 Palmitoylation
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|---|---|
| ln Vitro |
Since VT103 (HEK293T cells; 3 μM) does not prevent TEAD2, TEAD3, or TEAD4 from being palmitoylated, it seems to be TEAD1-selective. The YAP-TEAD1 connection is specifically disrupted by VT103 (NF2-deficient NCI-H226 cells; 3 mmol/L; 4 or 24 hours) [1]. Non-palmitoylated TEAD1 increases concurrently with the decrease of palmitoylated TEAD1 due to VT103 [1]. With an IC50 of 1.02 nM in the YAP reporter gene experiment, VT103 was demonstrated [1].
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| ln Vivo |
VT103 (0.3~10 mg/kg; administered orally once day) can decrease tumor growth even at a dose of 0.3 mg/kg [1]. Pharmacokinetics of VT103 in mice [1] Dose IV PO 7 mg/kg T1/2 (hour) Vdss (L/kg) CI (mL/min/kg) AUC 0-24 hours (μg*h/ mL) AUC 0- 24 hours (μg*h/mL) Oral availability (%) Cmax (ng/mL) C24 hours (ng/mL) 13.2 4.5 4.7 20.0 14.9 75 896 (1 hour) 340
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| Enzyme Assay |
Cell-free TEAD palmitoylation assay Purified recombinant TEAD1–YBD was first incubated with compounds and then with 2 μmol/L alkyne-palmitoyl-CoA. The reaction was quenched with 1% SDS followed by click chemistry reaction with biotin-azide as described previously. In some experiments, APCoA was added at different concentrations and in different sequence. Palmitoylated TEAD and total TEAD proteins were detected by streptavidin HRP and anti-TEAD1 antibody (Abcam) immunoblotting, respectively. |
| Cell Assay |
Cell-based TEAD palmitoylation assays Myc-TEAD expression plasmid transfected HEK293T cells were treated with DMSO or 100 μmol/L alkyne palmitate + DMSO/compound for 20 hours. Myc-TEAD protein was immunoprecipitated with anti-Myc antibody and subjected to click chemistry. Palmitoylated TEAD was detected by streptavidin immunoblotting. The Acyl-PEGyl Exchange Gel-Shift Assay was performed as described previously. |
| Animal Protocol |
Animal/Disease Models: NCI- H226 tumor-bearing mice [1]
Doses: 0.3~10 mg/kg Route of Administration: Po one time/day Experimental Results: Tumor growth can be prevented even at a dose of 0.3 mg/kg. Mouse pharmacokinetics VT103, VT104, and VT107, formulated in 5% DMSO + 10% Solutol + 85% D5W, were dosed intravenously or orally at 7 or 10 mg/kg. Blood was drawn from the saphenous vein at indicated timepoints. Compounds were quantified by LC/MS-MS using a QTRAP 6500. Data were analyzed using Phoenix WinNonlin 6.3, and intravenously noncompartmental model 201, and orally noncompartmental model 200. The calculation method was linear/log trapezoidal. In vivo pharmacodynamic and efficacy studies All the procedures related to animal handling, care, and the treatment were performed according to the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec or Crown Bioscience, Inc., following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). The testing article formulated in dosing solution (5% DMSO + 10% solutol + 85% D5W; D5W = 5% glucose) was orally administrated daily at the indicated doses. Tumor volume and animal weights were monitored twice weekly. |
| References |
| Molecular Formula |
C18H17F3N4O2S
|
|---|---|
| Molecular Weight |
410.413392782211
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| Exact Mass |
410.102
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| Elemental Analysis |
C, 52.68; H, 4.18; F, 13.89; N, 13.65; O, 7.80; S, 7.81
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| CAS # |
2290608-13-6
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| PubChem CID |
137534047
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| Appearance |
Off-white to gray solid powder
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| LogP |
3.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
617
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
LCVDQHLYHBAHR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H17F3N4O2S/c1-22-28(26,27)14-7-8-16(15(9-14)17-10-25(2)11-23-17)24-13-5-3-12(4-6-13)18(19,20)21/h3-11,22,24H,1-2H3
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| Chemical Name |
N-methyl-3-(1-methyl-1H-imidazol-4-yl)-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamide
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| Synonyms |
VT-103; VT 103; VT103
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~50 mg/mL (~121.83 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.09 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.1 mM) in 10% DMSO + 90% Corn oil, clear solution For example, if 1 mL of working solution is to be prepared, you can take 100 μL of 25 mg/mL of DMSO stock solution and add to 900 μL of corn oil, mix well (clear solution). (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4366 mL | 12.1829 mL | 24.3659 mL | |
| 5 mM | 0.4873 mL | 2.4366 mL | 4.8732 mL | |
| 10 mM | 0.2437 mL | 1.2183 mL | 2.4366 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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