Pharmacological Disruption of the Notch1 Transcriptional Complex Inhibits Tumor Growth by Selectively Targeting Cancer Stem Cells.
Pharmacological Disruption of the Notch1 Transcriptional Complex Inhibits Tumor Growth by Selectively Targeting Cancer Stem Cells.
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Notch1转录复合物的药理学破坏通过选择性靶向癌症干细胞抑制肿瘤生长。
DOI：
10.1158/0008-5472.can-20-3611
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发表时间：
2021-06-15
期刊：
影响因子：
11.2
通讯作者：
Capobianco AJ
中科院分区：
文献类型：
--
作者：
Alvarez-Trotta A;Guerrant W;Astudillo L;Lahiry M;Diluvio G;Shersher E;Kaneku H;Robbins DJ;Orton D;Capobianco AJ
在许多人类癌症中，Notch途径的失调已显示在肿瘤表型的起始和维持中起作用。异常的Notch活性在癌症干细胞的维持和存活中也起着核心作用，这是转移和对治疗的抗性的基础。由于这些原因，Notch信号传导的抑制已经成为癌症治疗开发的非常有吸引力的靶标。然而，开发Notch途径特异性药物的尝试在临床上基本上失败，部分原因是肠道毒性。在这里，我们报告NADI-351的发现，第一个具体的小分子抑制剂Notch 1转录复合物。NADI-351选择性地破坏Notch 1转录复合物并减少Notch 1向靶基因的募集。NADI-351在小鼠模型中表现出稳健的抗肿瘤活性而不诱导肠毒性，并且癌症干细胞通过NADI-351处理被消融。我们的研究表明，NADI-351是一种口服有效的Notch 1介导的转录抑制剂，可抑制肿瘤生长，毒性低，为改善癌症治疗提供了一种潜在的治疗方法。
In many human cancers, deregulation of the Notch pathway has been shown to play a role in the initiation and maintenance of the neoplastic phenotype. Aberrant Notch activity also plays a central role in the maintenance and survival of cancer stem cells, which underlie metastasis and resistance to therapy. For these reasons, inhibition of Notch signaling has become an exceedingly attractive target for cancer therapeutic development. However, attempts to develop Notch pathway specific drugs have largely failed in the clinic, in part due to intestinal toxicity. Here we report the discovery of NADI-351, the first specific small molecule inhibitor of Notch1 transcriptional complexes. NADI-351 selectively disrupted Notch1 transcription complexes and reduced Notch1 recruitment to target genes. NADI-351 demonstrated robust anti-tumor activity without inducing intestinal toxicity in mouse models, and cancer stem cells were ablated by NADI-351 treatment. Our study demonstrates that NADI-351 is an orally available and potent inhibitor of Notch1-mediated transcription that inhibits tumor growth with low toxicity, providing a potential therapeutic approach for improved cancer treatment.