Aileron Publish Data Showing Stapled Peptides Achieve the First Direct Inhibition of the Notch1 Transcription Factor Oncogene
News Nov 12, 2009
Aileron Therapeutics has announced 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 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 times.
In cancer biology, it has been shown that more than 50% of T-cell acute lymphoblastic leukemias (T-ALL) have activating mutations in Notchii. 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 transcription factor assemblies, giving us good reason to expect that this technology will be useful for other currently undruggable targets across diseases such as cancer, inflammation, obesity, and infection.”
“The publication of a second major research article in Nature within a year demonstrates the momentum and potential for development of Stapled Peptides as a new drug modality,” said Joseph Yanchik, III, Chief Executive Officer of Aileron Therapeutics. “Stapled Peptides designed to target therapeutically important but previously undruggable transcription factors, such as Notch, is a major focus of Aileron’s R&D effort and is of significant interest as one of our potential early clinical development programs.”
In a study published in Nature in October 2008 titled “BAX Activation is Initiated at a Novel Interaction Site,” Aileron Therapeutics collaborators at the Dana Farber Cancer Institute demonstrated that a Stapled Peptide was able to uniquely target a new and fundamental activation mechanism of the programmed cell death or “apoptotic” pathway.
Aileron has developed Stapled Peptides designed to target specific transcription factors across multiple therapeutic areas, and is advancing these compounds in its preclinical programs.
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