Researchers at Harvard Medical School have discovered a small molecule, 4EGI-1, which targets 'weak' RNAs to prevent proteins that help tumours grow from ever being produced. Messenger RNA (mRNA) acts as a template molecule between the DNA of our genes and the proteins they produce to carry out their function. However, most proteins related to tumour growth are generated from weak mRNA molecules that are less efficient. The team discovered a small molecule that targets the weak mRNAs, preferentially interrupting its translation into proteins.
This mechanism represents a new strategy in fighting cancer: instead of binding to cell growth proteins to prevent them from working, it is a novel way of preventing those proteins from ever being produced. The method could also target several different types of cancer, including lung and blood cancers, as it targets a general characteristic of the disease, regardless of its cause.
Team leader Gerhard Wagner explained that while cancer-promoting proteins may be lost as a result of such treatment, so called "housekeeping" genes that cells need on a regular basis are more readily translated from 'strong' mRNAs and so remain unaffected.
Restricted to the cell nucleus, the double stranded DNA generates a single strand of RNA that acts as a mobile template for the gene. The mRNA then carries the gene's message to the ribosome - essentially a protein factory - and translates the message into proteins. These proteins then carry out the function specific to each gene.
Weak mRNAs have a long, highly structured region that is not used in protein translation and only serves as an obstacle to the ribosomal machinery. Contrastingly, strong mRNAs have only short untranslated regions. In order for a weak mRNAs to be successfully translated it relies on other proteins called initiation factors.
The researchers searched through thousands of small molecules before identifying 4EGI-1. This molecule prevents a specific pair of these initiation factors, eIF4E and eIF4G, from forming a complex that is known to play a key role in protein production.
The positive lab results were then repeated in tests on mammalian cells, where protein production from two genes related to cancer growth, c-Myc and Bcl-xL , declined and other genes were unaffected.
Wagner said that the strategy is "unusual in that it targets a protein-protein interaction, which has not typically been considered a good drug target."
However, the molecule needs further development before it acts strongly enough to be used as a drug. The team are currently working at modifying the compound to increase its efficacy and are also screening molecule libraries in search of more potent compounds before beginning tests on animals.
In addition, small molecule inhibitors of the eIF4E/eIF4G complex could be used as a genetic tool to investigate protein production controls in various cellular processes, such as embryonic development.
