Novel Stapled BH3 Peptides Therapeutics for Targeting Mcl-1 as a Potential Treatment for Multiple Cancers

Web Published:

12/20/2012

Description:

Novel Stapled BH3 Peptides Therapeutics for Targeting Mcl-1 as a Potential Treatment for Multiple Cancers

Princeton Docket # 12-2785-1

Researchers in the Department of Chemical and Biological Engineering Princeton University have identified novel stapled peptides, which have been engineered to have high cytotoxic activity against several different cancer cell lines (unpublished data).

In studying the effect of increasing the affininty of a BH3 peptide towards pro-survival proteins, five peptides have been identified, two of which are able to kill four cancer cell lines with an IC50 in the single micromolar range.

BH3 proteins are a collection of pro-death proteins in the Bcl-2 family that play important roles in inducing apoptosis. Proactive heterodimeric interactions between pro-death and pro-survival protein members of the Bcl-2 family members can be a cause of cancer. A promising therapeutic intervention in cancers focuses on inhibition of such heterodimeric interactions between family members via the binding of a BH3 peptide or a small molecule BH3 peptide mimic. Conformationally constrained stapled BH3 peptides take effect through inhibiting the sequestration of pro-death proteins by pro-survival proteins, and restoration of apoptotic function to the cells.

Applications

· Novel therapeutics for solid tumor cancers, such as breast, cervical, and prostate.

Advantages

· Lower cost of production, due to small size.

· Lower dosing requirements.

· Potential improved pharmacological properties.

Stage of Development

Further in vivo animal studies are planned pending further industrial or academic collaborations.

The Inventors

A. James Link is an Assistant Professor of Chemical and Biological Engineering in Princeton University. The research in the Link group is highly interdisciplinary and focuses on protein engineering and chemical biology. One of the major focuses of the Link group is to apply directed evolution, an experimental algorithm that mimics Darwinian evolution, to medically relevant proteins. His research approach is to engineer proteins by utilizing directed evolution to introduce new functions into proteins. The library of protein variants is then screened to identify those members of the population with the highest levels of function or activity. Dr. Link has been recognized by NSF CAREER Award in 2010 and been appointed as DuPont Young Professor in 2011.