Ras protein discovery could lead to drug
US researchers have taken the first steps towards designing a drug to target one of the most important proteins in cancer.
UK experts called the finding 'exciting' but cautioned there was a long way to go to convert the discovery into something that would benefit patients.
In findings presented at the American Society for Cell Biology's (ASCB) conference in Denver, the Genentech team said the discovery offers hope that a drug could be developed to target the Ras family of proteins.
In order to develop such a drug to turn off Ras, experts need to find a binding site, or opening, to which a therapeutic molecule can be attached.
Genentech researchers Joachim Rudolph, Weiru Wang and Guowei Fang told the ASCB meeting that they have found a possible opening.
Using a technique called fragment-based drug discovery, they tested thousands of small molecules for their potential to stick to Ras.
Out of 3,300 small molecule compounds that they screened, they found 25 candidates. None of them switched off the mutated Ras protein, but crucially the scientists discovered that they all bound to the same location.
They are now hoping to build up these molecules into something that could help switch off a mutated Ras protein and ultimately provide an effective cancer treatment, although they acknowledge there are many hurdles ahead.
The principal barrier is the fact that the molecules identified by the Genentech team do not stick bind to the area of Ras that passes signals on to other proteins. Instead, they target the area that receive signals from other proteins.
However, Dr Fang said hopes have been raised that a weakness exists in what researchers had feared was the "undruggable" Ras.
"The small molecules identified here represent the first generation of Ras inhibitors that directly prevent Ras activation," he said.
Professor Julian Downward, a cell-signalling expert based at Cancer Research UK's London Research Institute, pointed to the long history of research on Ras. "Researchers around the world - including my own lab and others supported by Cancer Research UK - have been studying Ras for more than 25 years, understanding how it drives cancer and working on ways to target it with drugs.
"This new research represents a very exciting 'proof-of-concept' that Ras can indeed be targeted, but these particular molecules could never, on their own, act as cancer drugs," he added.
"On top of this, the molecules work by preventing Ras from 'listening' for growth signals and passing them on. But the faulty Ras proteins in cancer cells are 'deaf' to these signals, and instead broadcast non-stop growth messages. So researchers still need to work out how to turn off these faulty Ras proteins, if this is ever to be developed into a cancer treatment."
Commenting on the way the researchers isolated the molecules, Professor Martin Drysdale, head of the Cancer Research UK-funded drug discovery programme at the Beatson Institute in Glasgow, said that 'fragment-based' drug discovery was gaining traction as a way "to target cancer proteins that have been regarded as 'undruggable'.
"In recent years this approach has led to the targeted therapy vemurafenib, which was recently approved in the US to treat certain forms of skin cancer.
"My lab is also working on Ras, along with other important cancer targets, and it's great to hear about Genetech's progress. The coming years will be extremely exciting, as discoveries in the lab can be harnessed using approaches like fragment-based discovery to create more experimental drugs for clinical trials, that we hope will benefit patients," he added.
Copyright Press Association 2011
- T. Maurer et al. Drugging the Undruggable: Small-Molecule Inhibition of the Ras Oncoprotein. American Society for Cell Biology meeting 2011 (download abstract PDF)