New type of promising compound against prostate cancer / ScienceDaily

"Rather than continuing to make compounds that look like older drugs, our job has been to rethink the definition of what a drug-like molecule may be," said Susan K. Logan, corresponding author, PhD, associate professor at NYU Langone Department of Urology.

A joint research team from the NYU School of Medicine and New York University discovered that their "cyclic peptoids" reduced the growth of prostate cancer cells in cultures by 95% compared to untreated cells . Experimental drugs have also blocked an important growth signal associated with testing in live animals.

"We designed our peptoids specifically to hit targets that are currently" unbearable, "" such as those causing treatment-resistant prostate cancer, "adds lead co-author Kent Kirshenbaum, PhD, a professor in the department's chemistry department. University of New York.

According to the team's report, published online Oct. 23 in Nature Communications, study compounds blocked growth by interfering with the interaction between beta-catenin protein and T cell factor (TCF) transcription factors, proteins that activate the genes responsible for cell multiplication .

Although genes are essential for the early development of prostate tissue, this gene activity is normally reduced to adulthood unless changes are activated, which can lead to cancer.

First test

Unlike many existing drugs, the new compounds do not target the androgen hormone signals known to promote prostate cancer. Most patients treated with antiandrogenic drugs have their cancer growth resume after a few months. The field has therefore sought other therapeutic strategies. Many efforts have focused on the abnormal signaling of the Wnt protein that occurs in 20% of the most resistant prostate tumors, but none has been transmitted to the clinic.

Wnts can cause the accumulation of beta-catenin protein in cell nuclei, where it activates genes. Prior to the new study, the research team had spent years designing a new class of robust and adjustable peptide compounds, called peptoids, that are just large enough to interact with the large flat surfaces used by beta-catenin for interact with TCFs. .

In addition, researchers knew that their compound should be designed not only to include the right chemical components, but also to bend into a desired three-dimensional shape. The researchers "stapled" together the ends of a linear peptoid molecule to form a loop-shaped or cyclic structure. This form resembled the proteins in the hairpins on which TCFs depend to interact with beta-catenin. The stapling stiffened the peptoid so that it could occupy and block the docking site that the TCF would otherwise use.

A new generation of computer simulation tools allowed the team to see early on how drug candidates could fit into their protein target. After these virtual tests, the team then synthesized the compounds for experiments in artificial environments filled with nutrients, called spheroids, in which cancer cells grow in three dimensions. Spheroids are more realistic than in two-dimensional Petri dishes.

In these experiments, cyclic peptoids reduced the growth of prostate cancer cells resistant to treatment by approximately 95% compared to untreated cancer cells over a 22-day period, compared with a growth reduction of only 40 % of the cells treated with the non stapled version of the peptoid. The compounds also decreased the hormonal signaling of androgens, suggesting a dual anti-cancer effect, according to the authors.

The researchers also wanted to show that their main compound could block the signals of beta-catenin in a living animal. They chose zebrafish, in which rare genetic changes (mutations) that allow beta-catenin to accumulate are known to prevent the formation of eyes. In repeated experiments on fish with such mutations, the team found that their peptoids looped – by blocking overactive beta-catenin, a similar TCF interaction to that affecting human prostate cancer – allowed the development of the eye.

In addition, the treatment showed no toxicity in zebrafish at a dose roughly corresponding to a dose that could function clinically in humans. In the future, the team will soon test their peptoids on mouse prostate cancer cells. In addition, tests are planned to determine if the compound can block beta-catenin, an interaction of TCF known to promote growth of colon and breast cancers.

The design of a new class of drugs required a multidisciplinary effort. Logan is an expert in prostate cancer and has helped select beta-catenin as a cyclic peptoid target. Study author and androgen expert, Michael J. Garabedian, PhD of the Langone Microbiology Department at Langone, has long been working with the New York University Chemistry Team, led by the main author of the study, Kent Kirshenbaum, who designed the peptoids.

The first author, Jeffrey Schneider, was a medical student / doctoral student in Dr. Logan's lab. He did most of the experimental work on the project. and co-first author, Tim Craven of the Department of Chemistry at the University of New York, designed the active cyclic peptoid. Craven is a student in the laboratory of Richard A. Bonneau, PhD, at the Center for Genomics and Systems Biology at New York University.

Holger Knaut, PhD, an assistant professor at NYU Langone's Institute of Biomolecular Medicine Skirball, led the work on zebrafish. Other authors of the study include Amanda Kasper, PhD, and Michael Haugbro of the Department of Chemistry at the University of New York; Chi Y. Yun, of the Institute of Biomolecular Medicine of Skirball; and Erica Briggs from NYU Langone's Department of Urology.

This work was funded by National Institutes of Health Grants CA112226, T32GM007308, 5T32CA009161 and NS069839 and a grant from the National Science Foundation, CHE-1507964. The Strand Flower Scholarship of the Department of Biology at the University of New York and the Horizon Scholarship funded by the NYU Graduate School of Arts and Sciences funded by the Natural and Physical Sciences curriculum.