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

CAMBRIDGE, MA November 11, 2009 Aileron Therapeutics, a biopharmaceutical company leading the development of a new class of drugs called Stapled Peptides, announced today that its collaborators, James E. Bradner, MD of the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT, and Gregory L. Verdine, PhD, Professor of Chemistry at Harvard University, published research in Nature entitled, "Direct Inhibition of the Notch Transcription Factor Complex." Results presented in the paper showed that Stapled Peptides can potently and directly inhibit the transcription factor Notch, an oncogene implicated in cancer cell proliferation and survival. This research validates the potential for Stapled Peptides to modulate key intracellular biological targets, such as transcription factors, that have not been addressable with current small molecule or biologic drug modalities. There are estimated to be more than 1,500 transcription factors in the human genome, regulating key biological processes important in diseases such as arthritis, asthma, diabetes, infectious diseases, and cancer .

In their research published in Nature, Drs. Bradner and Verdine showed in multiple models, including T-cell acute lymphoblastic leukemia (T-ALL), that Stapled Peptides achieved tight direct binding to the Notch transcription factor complex, preventing the assembly of a functional transcription complex by the Notch1 oncogene. Further in vivo data show that direct and specific antagonism of the Notch multi-protein complex in the nucleus of cancer cells suppressed the transcription of many growth stimulating proteins such as Myc, thereby leading to cancer cell death. Potent, specific pathway inhibition was determined using genome-wide transcriptional signatures, first in vitro and later validated as biomarker studies in vivo. The direct inhibition achieved did not result in gastrointestinal toxicity, suggesting a viable therapeutic window for Stapled
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