R&D Results

Aileron’s Stapled Peptide platform has been validated with positive data from a diverse range of novel drug candidates that were generated from the platform.

For example, a Stapled Peptide derived from the BID protein has demonstrated excellent in vitro and in vivo efficacy in multiple cancer models, including leukemia, and also avoids known resistance pathways. (Kapeller, R. et. al, American Association for Clinical Cancer Research 2008). This Stapled Peptide has been shown to functionally mimic the pro-apoptotic protein BIM, targeting the last committed step in programmed cell death to induce apoptosis.

A Stapled Peptide derived from the p53 transcription factor has also demonstrated positive results. p53 induces apoptosis in response to DNA damage or cellular stress and, as a result, plays a critical role in protecting cells from tumor development. Loss of p53 activity is the most common defect in human cancer. This Stapled Peptide has shown the ability to disrupt the interaction between p53 and both of its natural protein suppressors, hDM2 and hDMX (Kapellar, R. et. al., American Society of Hematology meeting 2008), thereby up-regulating p53 activity and inducing apoptosis in osteosarcoma in a specific, target-dependent manner.

A Stapled Peptide derived from the Mastermind coactivator protein can potently and directly inhibit NOTCH, an oncogene implicated in cancer cell proliferation and survival (G.L. Verdine, J.E. Bradner, et al., Nature, 2009). This Stapled Peptide selectively kills T-cell acute lymphoblastic leukemia (T-ALL), a cancer that is driven by the NOTCH signal transduction pathway. Transcriptional profiling of treated T-ALL cells in vitro and in vivo indicated that the anti-proliferative activities of this Stapled Peptide are specific and target-dependent.

Both the p53 and NOTCH Stapled Peptide programs validate the use of Stapled Peptides to selectively modulate transcriptional complexes in cell nuclei, including protein-protein or protein-DNA interactions, an approach that has essentially been “undruggable” by small molecules. The ability to specifically "turn on" or "turn off" gene expression by targeting transcriptional complexes has been a major unsolved challenge in drug discovery, and Aileron is well positioned to generate first-in-class therapeutics that modulate these master regulators.