Targeting the YAP-TEAD interaction interface for therapeutic intervention in glioblastoma.
Targeting the YAP-TEAD interaction interface for therapeutic intervention in glioblastoma.
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DOI：
10.1007/s11060-021-03699-6
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发表时间：
2021-04
影响因子：
3.9
通讯作者：
Gera J
中科院分区：
文献类型：
--
作者：
Saunders JT;Holmes B;Benavides-Serrato A;Kumar S;Nishimura RN;Gera J
最近的研究表明，Hippo 通路信号失调可能导致胶质母细胞瘤增殖和侵袭特征。该通路的下游效应子，Yes 相关蛋白 (YAP) 癌蛋白，已成为多形性胶质母细胞瘤 (GBM) 的一个有前景的靶标。利用基于高通量酵母双杂交的筛选，鉴定出一种小分子，该小分子可抑制共转录激活剂 YAP1 和 TEA 结构域家族成员 1 (TEAD1) 转录因子蛋白-蛋白相互作用界面的关联。这种候选抑制剂 NSC682769 是一种新型苯并氮杂化合物，对其影响 Hippo/YAP 轴信号传导的能力和潜在的抗胶质母细胞瘤特性进行了评估。 NSC682769 在体外和用亚微摩尔浓度处理的 GBM 细胞中有效阻断 YAP 和 TEAD 的关联。此外，抑制剂偶联珠下拉和表面等离子共振分析表明 NSC682769 与 YAP 结合。 NSC682769 对 GBM 系和患者衍生细胞的治疗导致 YAP 表达水平下调，从而导致 YAP-TEAD 转录活性减弱。在 GBM 细胞模型中，NSC682769 抑制增殖、集落形成、迁移、侵袭并增强细胞凋亡。在肿瘤异种移植和基因工程小鼠模型中，NSC682769 表现出显着的抗肿瘤反应，导致总体存活率增加，并表现出显着的血脑屏障渗透性。这些结果表明，阻断 YAP-TEAD 关联是胶质母细胞瘤的可行治疗策略。在这些有利的临床前研究的基础上，有必要进行进一步的临床研究。
Recent studies have suggested that dysregulated Hippo pathway signaling may contribute to glioblastoma proliferation and invasive characteristics. The downstream effector of the pathway, the Yes-associated protein (YAP) oncoprotein, has emerged as a promising target in glioblastoma multiforme (GBM). Utilizing a high-throughput yeast two-hybrid based screen, a small molecule was identified which inhibits the association of the co-transcriptional activator YAP1 and the TEA domain family member 1 (TEAD1) transcription factor protein–protein interaction interface. This candidate inhibitor, NSC682769, a novel benzazepine compound, was evaluated for its ability to affect Hippo/YAP axis signaling and potential anti-glioblastoma properties. NSC682769 potently blocked association of YAP and TEAD in vitro and in GBM cells treated with submicromolar concentrations. Moreover, inhibitor-coupled bead pull down and surface plasmon resonance analyses demonstrate that NSC682769 binds to YAP. NSC682769 treatment of GBM lines and patient derived cells resulted in downregulation of YAP expression levels resulting in curtailed YAP-TEAD transcriptional activity. In GBM cell models, NSC682769 inhibited proliferation, colony formation, migration, invasiveness and enhanced apoptosis. In tumor xenograft and genetically engineered mouse models, NSC682769 exhibited marked anti-tumor responses and resulted in increased overall survival and displayed significant blood-brain barrier penetration. These results demonstrate that blockade of YAP-TEAD association is a viable therapeutic strategy for glioblastoma. On the basis of these favorable preclinical studies further clinical studies are warranted.
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影响因子：
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