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Pharmacological Disruption of the Notch1 Transcriptional Complex Inhibits Tumor Growth by Selectively Targeting Cancer Stem Cells

2021; American Association for Cancer Research; Volume: 81; Issue: 12 Linguagem: Inglês

10.1158/0008-5472.can-20-3611

1538-7445

Annamil Alvarez-Trotta, William Guerrant, Luisana Astudillo, Mohini Lahiry, Giulia Diluvio, Elena Shersher, Hugo Kaneku, David J. Robbins, Darren Orton, Anthony J. Capobianco,

Epigenetics and DNA Methylation

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 (CSC), 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 antitumor activity without inducing intestinal toxicity in mouse models, and CSCs 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. SIGNIFICANCE: This study showcases the first Notch1-selective inhibitor that suppresses tumor growth with limited toxicity by selectively ablating cancer stem cells.