K-975
目录号 : GC62132
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。
Cas No.:2563855-03-6
Sample solution is provided at 25 µL, 10mM.
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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]。
| Cell experiment [1]: | |
Cell lines | Lentivirus (Sartorius) modified NCI-H2030 (NCI-H2030-CC) and NCI-H1792 (NCI-H1792-CC) |
Preparation Method | Cell cycle analysis was performed using lentivirus (Sartorius) modified NCI-H2030 (NCI-H2030-CC) and NCI-H1792 (NCI-H1792-CC). The conditions analyzed were DMSO, 100nM of K-975, 30nM of adagrasib, and COMBO (selected doses of adagrasib and K-975). At least two biological replicates were analyzed for each condition at 24, 48, and 72h. Inhibitors of Aurora B kinase (SML0268) and PLK1 (RO-3280) were used as controls. |
Reaction Conditions | 100nM; 24, 48, 72h |
Applications | In a time-course experiment up to 72h, we observed that every single agent led to a slight arrest in the G1 phase post-treatment. The combination of adagrasib and K-975 showed more robust G1 phase arrest than single agents. |
| Animal experiment [2]: | |
Animal models | SCID mice |
Preparation Method | Mice were subcutaneously injected into the right flank with 5×106 NCI-H226 cells in PBS containing 50% (v/v) BD Matrigel basement membrane matrix or 5×106 MSTO-211H cells in PBS containing 50% (v/v) BD high-concentration Matrigel basement membrane matrix. When the tumor volumes reached 100-200mm3, mice were orally administered K-975 (100mg/kg, twice a day, daily) or palbociclib (150mg/kg, once a day, daily) alone or in combination. The tumor volumes and body weights of mice were measured every 3-4 days. |
Dosage form | 100mg/kg; twice a day; p.o. |
Applications | K-975 exerts an anti-tumor effect and significant survival benefit in human mesothelioma xenograft mice. K-975 suppressed the tumor growth in NCI-H226 and MSTO-211H xenograft models. |
References: | |
| 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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| 制备储备液 | |||
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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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动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
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2.
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