K-975 is a potent and orally active inhibitor of YAP1/TAZ-TEAD protein-protein interaction[1]. Transcription enhancer-associated domain (TEAD) is a transcriptional activator of the Hippo pathway, which forms a complex with the transcriptional coactivator yes-associated protein (YAP) or the transcriptional coactivator PDZ-binding motif (TAZ), and their overactivation is associated with carcinogenesis[2]. K-975 showed effective antitumor effects in malignant pleural mesothelioma[3]. K-975 was able to attenuate the increase in connective tissue growth factor (CTGF) expression in retinal epithelial cells[4].
In vitro, K-975 (100nM) treatment of lentiviral-modified NCI-H2030 cells and NCI-H1792 cells for 24-72h resulted in a mild G1 phase arrest, and the combination with Adagrasib showed more significant effects than single drugs[5]. Treatment of NCI-H226 cells with K-975 (1-10000nM) for 24h reduced the expression of connective tissue growth factor (CTGF), insulin-like growth factor binding protein-3 (IGFBP3) and natriuretic peptide B (NPPB) mRNA, and increased the expression of F-box protein-32 (FBXO32) mRNA[6].
In vivo, oral administration of K-975 (100mg/kg) to treat human mesothelioma xenograft mice significantly inhibited tumor growth and improved survival in mice[6].
References:
[1] Bulakhova A, Cho J S, Rifkin J T, et al. Targeting the YAP/TAZ-TEAD pathway with TEAD inhibitors synergizes with chemotherapy and blocks diffuse gastric cancer progression[J]. Cancer Research, 2024, 84(6_Supplement): 7281-7281.
[2] Otsuki H, Uemori T, Inai Y, et al. Reversible and monitorable nephrotoxicity in rats by the novel potent transcriptional enhanced associate domain (TEAD) inhibitor, K-975[J]. The Journal of Toxicological Sciences, 2024, 49(4): 175-191.
[3] Kaneda A, Seike T, Uemori T, et al. Discovery of a first-in-class TEAD inhibitor which directly inhibits YAP/TAZ-TEAD protein-protein interaction and shows a potent anti-tumor effect in malignant pleural mesothelioma[J]. Cancer Research, 2019, 79(13_Supplement): 3086-3086.
[4] Murakami Y, Imaizumi T, Hashizume K, et al. Inhibition of Connective Tissue Growth Factor Expression in Adult Retinal Pigment Epithelial-19 Cells by Blocking Yes-Associated Protein/Transcriptional Coactivator with PDZ-Binding Motif Activity[J]. Journal of Ocular Pharmacology and Therapeutics, 2024, 40(4): 246-252.
[5] Tammaccaro S L, Prigent P, Le Bail J C, et al. TEAD inhibitors sensitize KRASG12C inhibitors via dual cell cycle arrest in KRASG12C-mutant NSCLC[J]. Pharmaceuticals, 2023, 16(4): 553.
[6] Kaneda A, Seike T, Danjo T, et al. The novel potent TEAD inhibitor, K-975, inhibits YAP1/TAZ-TEAD protein-protein interactions and exerts an anti-tumor effect on malignant pleural mesothelioma[J]. American Journal of Cancer Research, 2020, 10(12): 4399.
K-975是一种有效的具口服活性的YAP1/TAZ-TEAD蛋白-蛋白相互作用抑制剂[1]。转录增强相关结构域（TEAD）是Hippo通路的转录激活因子，它与转录辅激活因子yes相关蛋白（YAP）或转录辅激活因子PDZ结合基序（TAZ）形成复合物，它们的过度激活与致癌作用有关[2]。K-975在恶性胸膜间皮瘤中显示出有效的抗肿瘤效应[3]。K-975能够减弱视网膜上皮细胞中结缔组织生长因子（CTGF）表达的增加[4]。
在体外，K-975（100nM）处理慢病毒修饰的NCI-H2030细胞和NCI-H1792细胞24-72h，导致了G1期轻微停滞，和Adagrasib的组合比单一药物表现出更显著的效果[5]。K-975（1-10000nM）处理NCI-H226细胞24h，降低了结缔组织生长因子（CTGF）、胰岛素样生长因子结合蛋白-3（IGFBP3）和利钠肽B（NPPB）mRNA的表达，增加了F-box蛋白-32（FBXO32）mRNA的表达[6]。
在体内，K-975（100mg/kg）通过口服治疗人类间皮瘤异种移植小鼠，显著抑制了小鼠体内肿瘤生长并提高了存活率[6]。