VT103 is a selective TEAD1 protein palmitoylation inhibitor. VT103 inhibits YAP/TAZ-TEAD-mediated gene transcription, blocks TEAD auto-palmitoylation, and disrupts the interaction between YAP/TAZ and TEAD[1-2]. VT103 can be used in research related to HER2-positive breast cancer, prostate cancer, and triple-negative breast cancer[3-4].
In vitro, VT103 (10μM) was used to treat neonatal mouse cardiac fibroblasts (NMCFs) stimulated with angiotensin II (Ang-II; 100nM) for 48 hours. VT103 reversed the Ang-II-induced increase in α-SMA expression and inhibited collagen gel contraction and cell migration[5]. VT103 (10μM) was also used to treat human coronary artery smooth muscle cells (HCASMCs) overexpressing METTL14 for 24 hours. VT103 inhibited the expression of TEAD1, PDGFRB, CTGF, and Cyr61, restored the expression of contractile markers ACTA2, CNN1, and SM22α, and attenuated the METTL14 overexpression-enhanced cell viability, proliferation, and migration[6].
In vivo, VT103 (100mg/kg) combined with Dabrafenib (30mg/kg) was administered orally daily for 14 days to treat female BALB/c-nu mice bearing KTOR81 xenograft tumors. VT103 significantly inhibited tumor growth and maintained sustained tumor regression during a 42-day observation period, without significantly affecting mouse body weight[7]. VT103 (0.3, 1, 3mg/kg) was administered orally daily for 45 days to treat mice bearing NCI-H226 xenograft tumors. VT103 significantly inhibited tumor growth, and at the 3mg/kg dose, VT103 induced tumor regression without significantly affecting body weight during the treatment period[8].
References:
[1] Heinrich T, Peterson C, Schneider R, et al. Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106. J Med Chem. 2022 Jul 14;65(13):9206-9229.
[2] Vaparanta K, Song Z, Farahani I, et al. Phosphoproteomic analysis reveals the diversity of signaling behind ErbB-inhibitor-induced phenotypes. FEBS J. 2025 Dec;292(24):6557-6575.
[3] Zhang S, Tan YQ, Zhang X, et al. TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma. Oncogene. 2025 Mar;44(11):753-768.
[4] Evsen L, Morris PJ, Thomas CJ, et al. Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma. Pharmaceuticals (Basel). 2023 Nov 21;16(12):1635.
[5] Song S, Zhang X, Huang Z, et al. TEA domain transcription factor 1(TEAD1) induces cardiac fibroblasts cells remodeling through BRD4/Wnt4 pathway. Signal Transduct Target Ther. 2024 Feb 19;9(1):45.
[6] Wang L, Xia G, Tang Y, et al. METTL14 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation via m6A Methylation TEAD1 mRNA. J Biochem Mol Toxicol. 2025 May;39(5):e70284.
[7] Hosoya K, Ozasa H, Yoshida H, et al. Novel TEAD1 Inhibitor VT103 Enhances Dabrafenib Efficacy in BRAF V600E Mutated Lung Adenocarcinoma via Survivin Downregulation. Cancer Sci. 2025 Jul;116(7):1883-1896.
[8] Tang TT, Konradi AW, Feng Y, et al. Small Molecule Inhibitors of TEAD Auto-palmitoylation Selectively Inhibit Proliferation and Tumor Growth of NF2-deficient Mesothelioma. Mol Cancer Ther. 2021 Jun;20(6):986-998.
VT103是一种选择性TEAD1蛋白棕榈酰化抑制剂。VT103可抑制YAP/TAZ-TEAD促进的基因转录、阻断TEAD自棕榈酰化并破坏YAP/TAZ与TEAD之间的相互作用[1-2]。VT103可用于HER2阳性乳腺癌、前列腺癌和三阴性乳腺癌的相关研究[3-4]。
在体外，VT103（10μM）处理经血管紧张素II（Ang-II；100nM）刺激的新生小鼠心脏成纤维细胞（NMCFs）48小时。VT103可逆转Ang-II诱导的α-SMA表达增加，同时抑制胶原凝胶收缩和细胞迁移[5]。VT103（10μM）处理过表达METTL14的人冠状动脉平滑肌细胞（HCASMCs）24小时。VT103可抑制TEAD1、PDGFRB、CTGF、Cyr61表达，恢复收缩标志物ACTA2、CNN1、SM22α的表达，并减弱METTL14过表达所增强的细胞活力、增殖和迁移[6]。
在体内，VT103（100mg/kg）联合Dabrafenib（30mg/kg）每日口服给药，处理携带KTOR81异种移植瘤的雌性BALB/c-nu小鼠14天。VT103可显著抑制肿瘤生长，并在42天观察期内维持持续的肿瘤消退，同时未对小鼠体重产生显著影响[7]。VT103（0.3、1、3mg/kg）每日口服给药，用于处理携带NCI-H226异种移植瘤的小鼠45天。VT103显著抑制了肿瘤生长，在3mg/kg剂量下导致了肿瘤消退，同时治疗期间未对小鼠体重产生显著影响[8]。