K-975
目录号 : GC62132K-975 is a potent, selective and orally active TEAD inhibitor that directly inhibits YAP/TAZ-TEAD protein-protein interaction and shows a potent anti-tumor effect in malignant pleural mesothelioma.
Cas No.:2563855-03-6
Sample solution is provided at 25 µL, 10mM.
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K-975 is a potent, selective and orally active TEAD inhibitor that directly inhibits YAP/TAZ-TEAD protein-protein interaction and shows a potent anti-tumor effect in malignant pleural mesothelioma.
[1] Kaneda A, et al. 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3086.
Cas No. | 2563855-03-6 | SDF | |
分子式 | C16H14ClNO2 | 分子量 | 287.74 |
溶解度 | DMSO : 220 mg/mL (764.58 mM; Need ultrasonic) | 储存条件 | Store at -20°C, protect from light |
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1 mg | 5 mg | 10 mg | |
1 mM | 3.4754 mL | 17.3768 mL | 34.7536 mL |
5 mM | 0.6951 mL | 3.4754 mL | 6.9507 mL |
10 mM | 0.3475 mL | 1.7377 mL | 3.4754 mL |
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The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma
Am J Cancer Res 2020 Dec 1;10(12):4399-4415.PMID:33415007doi
The Hippo signaling pathway regulates cell fate and organ development. In the Hippo pathway, transcriptional enhanced associate domain (TEAD) which is a transcription factor is activated by forming a complex with yes-associated protein 1 (YAP1) or transcriptional coactivator with PDZ-binding motif (TAZ, also called WWTR1). Hyper-activation of YAP1/TAZ, leading to the activation of TEAD, has been reported in many cancers, including malignant pleural mesothelioma (MPM). Therefore, the YAP1/TAZ-TEAD complex is considered a novel therapeutic target for cancer treatment. However, few reports have described YAP1/TAZ-TEAD inhibitors, and their efficacy and selectivity are poor. In this study, we performed a high-throughput screening of a neurofibromin 2 (NF2)-deficient MPM cell line and a large tumor suppressor kinase 1/2 (LATS1/2)-deficient non-small-cell lung cancer cell line using a transcriptional reporter assay. After screening and optimization, K-975 was successfully identified as a potent inhibitor of YAP1/TAZ-TEAD signaling. X-ray crystallography revealed that K-975 was covalently bound to an internal cysteine residue located in the palmitate-binding pocket of TEAD. K-975 had a strong inhibitory effect against protein-protein interactions between YAP1/TAZ and TEAD in cell-free and cell-based assays. Furthermore, K-975 potently inhibited the proliferation of NF2-non-expressing MPM cell lines compared with NF2-expressing MPM cell lines. K-975 also suppressed tumor growth and provided significant survival benefit in MPM xenograft models. These findings indicate that K-975 is a strong and selective TEAD inhibitor with the potential to become an effective drug candidate for MPM therapy.