4EgI-1

4EGI-1, a newly developed synthetic biological molecule, has recently been found to treat certain types of cancer by interrupting the binding of transcription factor proteins necessary for the rapid cell growth characteristic of tumors. The inhibition of these transcription factors prevents the initiation and translation of many proteins whose function is essential to the growth and proliferation of cancer cells.

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4EGI-1 works by binding to an initiation factor known as eIF4F. Under normal conditions this protein would bind to another initiation factor, known as eIF4G, to form an initiation complex. This complex is important in the initiation of translation of weak messenger RNAs. Disruption of the complex by 4EGI-1 was shown to preferentially down regulate growth, proliferation, and anti-apoptotic proteins.1

Messenger RNAs (mRNAs) are transcribed from DNA, and serve as templates for the synthesis of proteins by ribosomal translation. Weak mRNAs contain long and highly structured “untranslated regions” at their 5’ end. This lengthy region makes it difficult for enzymes to determine where transcription should begin. As a result, initiation factors are needed to help translation along. These weak mRNAs produce proteins that are involved in the development of cancer cells.2 Strong mRNAs, in contrast, are translated much easier, and generally code for proteins the cell needs on a regular basis. Therefore, therapies can be created that target only the production of the weak mRNAs while not disrupting the cell’s normal cycle.

The binding site of 4EGI-1 on the eIF4F is a smaller subset of the eIF4G binding site. Aside from blocking the formation of the eIF4F-eIF4G complex, 4EGI-1 enhances the binding of a molecule known as 4E-BP. This molecule, at high concentrations, has been effective at arresting tumor growth.

This molecule has been tested both in vitro and in vivo in several different types of cancer cells. 4EGI-1 has been shown to induce apoptosis in Jurkat leukemia cells and seems to inhibit proliferation of A549 lung cancer cells1.

This molecule was discovered by a group of researchers from Harvard Medical School using a novel high throughput screening method. (Put link to HTS Wikipedia here). Gerhard Wagner, a lead researcher and professor at Harvard Medical School’s Department of Biological Chemistry and Molecular Pharmacology, and his team screened 16,000 compounds searching for one that would disrupt the eIF4E-eIF4G interaction.

This molecule however is not strong enough to be used as an effective cancer treatment by itself. Researchers now will have to modify the inhibitor to enhance its actions as well as look for another more potent molecule3. Binding more efficiently with eIF4E would more specifically destroy the cancer cells without affecting normal cells. 4EGI-1 provides a new tool for studying translational control of proteins, and possibly provides a new strategy for cancer therapy4.