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Aileron collaborates study in Nature: Stapled peptides inhibit Notch1 transcription factor
Date:11/11/2009

Peptides, without the limitations previously observed with upstream inhibitors of Notch.

"Transcription factors are among the most desirable and validated therapeutic targets in cancer, yet they are among the most elusive targets in cancer drug discovery," said James Bradner, MD,, Division Of Hematologic Neoplasia, Dana-Farber Cancer Institute. "Our research shows, for the first time, how assembly of the Notch multi-protein transcription factor complex can be inhibited in the nucleus of a cancer cell with a stapled peptide, leading to cancer cell death. Using stapled peptides to target transcription factors opens a potential new path for discovering novel and effective therapies for patients."

A growing body of research describes the critical role that transcription factors play in biological pathways implicated in a broad array of human diseases. In the past 25 years, for example, the 20 most-cited transcription factors have been referenced in the scientific literature an estimated 100,000 timesi. In cancer biology, it has been shown that more than 50% of T-cell acute lymphoblastic leukemias (T-ALL) have activating mutations in Notch . However, the vast majority of transcription factors lack an appropriate binding pocket for targeting by small molecules. Moreover, most transcription factors reside within cells and so are not suitable for antibody-based therapies. Stapled Peptides have now been shown to inhibit a previously-undruggable transcription factor at a therapeutically meaningful level.

"These results are tantamount to a declaration of open season on transcription factors," said Gregory L. Verdine, PhD, Erving Professor of Chemistry, Harvard University and co-chair of Aileron Therapeutics' scientific advisory board. "While the vast majority of transcription factors are not druggable with current small molecule or biologic modalities, many features of the protein-protein interaction represented by Notch are similar to other transcr
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Source:Eurekalert

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