Scientists from USC and NYU design a molecule that blocks cancer growth in mice

May 12, 2014

A team of researchers from USC and NYU has developed and patented a small molecule that interferes with cancer progression with minimal side effects.

The molecule prevents two critical proteins from interacting by mimicking the surface topography of one protein - like wearing a mask - which tricks the other protein into binding with it. This stops a so-called "transcription factor" that controls the transcription of genetic information. That transcription factor is what would have created an aberrant gene expression, contributing to the cancer growth.

Because of the molecule's precision in targeting the protein interaction, the treatment does not appear to produce any side effects when tested animal tumor models.

"This complex represents one of the key focal points in the tumor-promotion," said Bogdan Olenyuk, assistant professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy, and one of two corresponding authors on a paper about the work. "However, targeting it for therapeutic intervention was a major challenge, since transcription factors do not possess the necessary topographical structures to make them good targets for mimicking drugs.

Instead, the team focused on blocking one of the transcription factor's binding partners - a large protein with complex topography that makes it an easier, more "druggable" target.

Teams of researchers from USC and NYU collaborated on the study. Olenyuk led the USC group, which included graduate students Ivan Grishagin and researcher Hanah Mesallati. Paramjit Arora, professor of chemistry at NYU and co-corresponding author on the paper, lead the NYU group, which included graduate student Brooke Bullock Lao and Thomas Brewer.

Their study appears this week in the Proceedings of the National Academy of Sciences (PNAS). The researchers have filed patent applications for the new design, which has already attracted the interest of several pharmaceutical companies.

Targeting the protein-protein interactions has been a longstanding goal of researchers in the field of cancer biology, and became the focus of Olenyuk's research since 2008.

"After completing my postdoctoral project in cancer gene regulation with my mentor Peter Dervan at Caltech and our collaborator Bill Kaelin at Harvard Medical School, I decided to make a major focus of my research on an interdisciplinary problem of targeting oncogenic transcription factors with designed drug-like molecules," he said.

The researchers used Rosetta Software, a design software for molecular structures, to guide their design. They then designed a strategy to graft the specially textured surface onto a stable scaffold.

So far, the molecules have only been tested animal models, but the researchers plan to take the appropriate steps to prepare for the next step - to translate these compounds into clinic.
-end-
This work was funded by the National Science Foundation (grants CHE-1161644 and CHE-1151554) and the NYU Perlmutter Cancer Center (grant 5P30CA16087-33).

University of Southern California

Related Protein Articles from Brightsurf:

The protein dress of a neuron
New method marks proteins and reveals the receptors in which neurons are dressed

Memory protein
When UC Santa Barbara materials scientist Omar Saleh and graduate student Ian Morgan sought to understand the mechanical behaviors of disordered proteins in the lab, they expected that after being stretched, one particular model protein would snap back instantaneously, like a rubber band.

Diets high in protein, particularly plant protein, linked to lower risk of death
Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.

A new understanding of protein movement
A team of UD engineers has uncovered the role of surface diffusion in protein transport, which could aid biopharmaceutical processing.

A new biotinylation enzyme for analyzing protein-protein interactions
Proteins play roles by interacting with various other proteins. Therefore, interaction analysis is an indispensable technique for studying the function of proteins.

Substituting the next-best protein
Children born with Duchenne muscular dystrophy have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles.

A direct protein-to-protein binding couples cell survival to cell proliferation
The regulators of apoptosis watch over cell replication and the decision to enter the cell cycle.

A protein that controls inflammation
A study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis.

Resurrecting ancient protein partners reveals origin of protein regulation
After reconstructing the ancient forms of two cellular proteins, scientists discovered the earliest known instance of a complex form of protein regulation.

Sensing protein wellbeing
The folding state of the proteins in live cells often reflect the cell's general health.

Read More: Protein News and Protein Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.