A collaboration between NYU Professors Kent Kirshenbaum (Chemistry), Richard Bonneau (Biology) and Susan K. Logan (Medicine) has made great strides in developing new prostate cancer therapeutics. Their work reveals a promising and practical way to antagonize protein/protein interactions, developing "cyclic peptoids" that can attack treatment-resistant prostate cancer. NYU graduate student Tim Craven (currently a postdoc at the University of Washington) is second author, and other Krishenbaum Group members Amanda Kasper and Michael Haugbro are among the authors. The study, called Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer, was published in Nature Communications. The research was highlighted in an article entitled New Type of Molecule Shows Early Promise Against Treatment-Resistant Prostate Cancer in News-Medical, and was picked up by NYU Research Highlights in New Kind of Compound Shows Early Promise Against Prostate Cancer.
Abstract: New chemical inhibitors of protein–protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the β-catenin:TCF interaction. The β-catenin:TCF interaction plays a critical role in the Wnt signaling pathway which is over-activated in multiple cancers, including prostate cancer. Using the Rosetta suite of protein design algorithms, we evaluate how different macrocycle structures can bind a pocket on β-catenin that associates with TCF. The in silico designed macrocycles are screened in vitro using luciferase reporters to identify promising compounds. The most active macrocycle inhibits both Wnt and AR-signaling in prostate cancer cell lines, and markedly diminishes their proliferation. In vivo potential is demonstrated through a zebrafish model, in which Wnt signaling is potently inhibited.
This research was supported by the National Institutes of Health, the National Science Foundation, the Blavatnik Family Foundation, and the Howard Hughes Medical Institute.