The transcriptional enhanced associate domain (TEAD) is a transcription factor. In mammals, TEAD has four different isoforms namely TEAD1 (TEF-1/NTEF), TEAD2 (TEF-4/ETF), TEAD3 (TEF-5/ETFR-1), and TEAD4 (TEF-3/ETFR-2/FR-19). And there is a high degree of homology and expression pattern between TEAD1-4. The TEAD families regulate cell growth, proliferation, and tissue homeostasis via their transcriptional target genes. In addition, the transcriptional output of TEAD plays an important role in tumor progression, metastasis, cancer metabolism, and immunity. Therefore, TEAD is an important target for the treatment of human diseases including cancer and cardiovascular diseases.

TEAD coordinates with various signal transduction pathways, including Hippo, Wnt, TGFβ, and EGFR pathways. But so far, TEAD is a key transcription factor of the Hippo pathway. Because in the Hippo pathway, TEAD is activated by forming a complex with YAP1 or transcriptional coactivator with PDZ-binding motif (TAZ). Accordingly, the YAP1/TAZ-TEAD complex is a novel therapeutic target for cancer treatment. Moreover, the YAP1/TAZ-TEAD complex is also an effective therapeutic target for malignant pleural mesothelioma (MPM).

K-975 is a potent, selective and orally active TEAD inhibitor.

K-975 effectively inhibits the protein-protein interactions between YAP1/TAZ and TEAD. And K-975 covalently binds to Cys359 located in the palmitate-binding pocket of TEAD. More importantly, K-975 exhibits antitumor activity in human MPM cell lines. K-975 strongly inhibits the reporter activity in NCI-H661/CTGF-Luc cells, but does not inhibit the reporter activity in NCI-H661/NRF2-Luc cells. In NCI-H226 cells, K-975 decreases the expressions of CTGF, IGFBP3, and NPPB mRNAs, and increases the expression of FBXO32 mRNA. Furthermore, K-975 potently inhibits the proliferation of NF2-non-expressing MPM cell lines. K-975 also strongly inhibits the proliferation of MSTO-211H cells, an NF2-expressing cell line.

To sum up, K-975 is a potent and orally active pan-TEAD inhibitor. K-975 shows anti-tumor effects by inhibiting YAP1/TAZ-TEAD signaling in SCID mice.

References：

[1] Ayumi Kaneda, et al. Am J Cancer Res. 2020 Dec 1;10(12):4399-4415.

[2] Hyunbin D Huh, et al. Cells. 2019 Jun 17;8(6):600.