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Updated: Nov 10, 2025

Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer

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

Annamil Alvarez-Trotta1,2, William Guerrant3, Luisana Astudillo1,2

  • 1The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida.

Cancer Research
|April 6, 2021
PubMed

Insights

Researchers discovered NADI-351, a novel Notch1 inhibitor that targets cancer stem cells (CSCs). This drug shows potent antitumor activity with low toxicity, offering a promising new approach for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Deregulation of the Notch pathway is implicated in human cancer initiation and progression.
  • Aberrant Notch activity supports cancer stem cell (CSC) survival, contributing to metastasis and treatment resistance.
  • Targeting the Notch pathway is a key strategy for cancer therapeutics, but clinical attempts have faced challenges including toxicity.

Purpose of the Study:

  • To identify and characterize a novel inhibitor targeting Notch1 transcriptional complexes.
  • To evaluate the efficacy and safety of this inhibitor in preclinical cancer models.
  • To assess the compound's ability to ablate cancer stem cells and reduce tumor growth.

Main Methods:

  • Discovery of NADI-351, a small-molecule inhibitor specific to Notch1 transcriptional complexes.
  • Assessment of NADI-351's ability to disrupt Notch1 recruitment to target genes.
  • Evaluation of NADI-351's antitumor activity, intestinal toxicity, and CSC-ablating effects in mouse models.

Main Results:

  • NADI-351 selectively inhibited Notch1 transcriptional complexes and reduced target gene recruitment.
  • The compound demonstrated significant antitumor activity in mouse models.
  • NADI-351 treatment effectively ablated CSCs without causing intestinal toxicity.

Conclusions:

  • NADI-351 is the first identified Notch1-selective inhibitor of transcriptional complexes.
  • This orally available agent potently inhibits Notch1-mediated transcription, suppressing tumor growth with low toxicity.
  • NADI-351 represents a potential therapeutic strategy for cancer by selectively targeting CSCs.

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