Researchers discover novel way to inhibit key cancer driver, other mutated genes

Researchers at the University of Boulder have discovered a new way to stop the growth of tumors, opening the door to new therapeutic strategies for cancer and a host of other diseases.

The discovery, published in the journal Cell Reports, marks an important step forward in the decades-long quest to target transcription factors.

One of the most high impact therapeutic targets in biomedicine is the class of proteins.

There are more than 1,500 transcription factors in the human body, each of which is responsible for binding to specific sequences in DNA.

It's important to understand that different TFs act in different kinds of cells, regulating everything from inflammation to cholesterol metabolism to wound healing to controlled cell death, which is key to preventing cancer.

Taatjes said that when a TF is altered, those instructions can go awry and turn it into a harmful one.

The p53 transcription factor is the subject of this study and can be changed into a tumor promoter.

Scientists have been trying to develop methods to stop the growth of transcription factors. Because they are all similar in the regions that bind to DNA, targeting one can indirectly target others. It's hard to develop a molecule that will block the activation domain of transcription factors because they contain a section.

Despite the huge potential and years of effort, therapeutic targeting of transcription factors has proven to be largely intractable.

A promising solution.

A group of scientists, including Alanna Schepartz, professor of chemistry at the University of California, Berkeley, have spent years developing a solution.

They set out to find a way to block p53, which is present in every cell and plays a critical role in human development.

Instead of targeting p53, they targeted the Mediator complex. The bridge between the p53 and other transcription factors and the enzyme that decodes sections of the body's genetic blueprint is called Mediator. The decoding process can be activated by the transcription factor clicking into Mediator, like a key in a lock.

In laboratory studies of human cancer cells, the researchers found that when they applied a novel peptide, which they designed based upon the p53 activation domain, they could prevent p53 from working. The team showed that blocking p53 from clicking in to Mediator was how thepeptide worked, like jamming up the lock before the real key could be inserted.

There has been a decades-long goal to target drug transcription factors directly. This does not affect other transcription factors in the cell.

Taatjes said that the work is a proof-of-concept study and that more research is needed before a strategy could be implemented in the clinic.

He said the approach could be applied to many other TFs that have been implicated in disease, opening the door to new treatment strategies for everything from heart disease to neurological disorders.

The method they used could lead to faster, cheaper ways to develop new leads for drugs.

The methods we discuss here could potentially apply to any disease that is driven by transcription factor function.

More information: Benjamin L. Allen et al, Suppression of p53 response by targeting p53-Mediator binding with a stapled peptide, Cell Reports (2022). DOI: 10.1016/j.celrep.2022.110630 Journal information: Cell Reports Citation: Researchers discover novel way to inhibit key cancer driver, other mutated genes (2022, April 7) retrieved 7 April 2022 from https://phys.org/news/2022-04-inhibit-key-cancer-driver-mutated.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.