A drug discovery team at Genentech, Inc., has uncovered a chink in the molecular armor of Ras, the most commonly occurring oncogene, which is a gene that when mutated has the potential of causing cancer in humans.
The chink, binding pocket of "functional significance" on the Ras oncoprotein could provide the long-sought attack point for a therapeutic agent, making the "undruggable" Ras oncogene "druggable," the researchers reported at the American Society for Cell Biology's 51st Annual Meeting in Denver.
The first human oncogene to be identified, Ras is mutated in about 25% of all human tumors. For cancer patients, the presence of an activated Ras oncogene is a poor prognosis marker.
Ras has a molecular on-off switch, activated by the energy transfer molecule GTP. In the "on" position, the oncogene activates critical cell signaling pathways involving cell proliferation, cell migration and cell differentiation, all of which are in hyper-drive in tumors.
To develop a drug that would switch off Ras, scientists needed a binding site, an opening in the Ras oncoprotein to which the docking mechanism of a therapeutic molecule could attach.
At the ASCB meeting, Joachim Rudolph, Ph.D., Weiru Wang, Ph.D., and Guowei Fang, Ph.D., of Genentech, a member of the Roche Group, reported that they identified such a binding pocket by fragment-based lead discovery, a screening process that sorted through 3,300 small molecule compounds. Nuclear magnetic resonance (NMR) spectroscopy was used to pinpoint molecules with even a weak affinity for binding to Ras oncoproteins. The researchers identified 25 compounds, none of which knocked out the oncoprotein.
However, NMR spectroscopy revealed that the 25 compounds were binding to the same location on the Ras oncoprotein. The researchers determined that the binding pocket was not static but could be enlarged once the ligand from the small molecule engaged it, providing researchers an opening for engineering the next generation of compounds.
Fang said that even the weak ligands formed by these compounds interfered with the Ras oncoprotein by blocking an enzyme, abbreviated SOS, that is required for activating the oncoprotein.
"The small molecules identified here represent the first generation of Ras inhibitors that directly prevent Ras activation," Fang said.
Guowei Fang, Ph.D. Genentech, Inc. Fang.firstname.lastname@example.org 650-228-8497
Robin Snyder, Ph.D. Director, External Communications Genentech Corporate Relations 650.467.7152 email@example.com
John Fleischman American Society for Cell Biology firstname.lastname@example.org 513-929-4635 513-706-0212 (cell)
Cathy Yarbrough American Society for Cell Biology email@example.com 858-243-1814
Sunday, Dec. 4, 2011 5:35 to 5:55 p.m. Minisymposium: Chemical Biology: Probes and Therapeutics Presentation 24
John Fleischman | EurekAlert!
Individual Receptors Caught at Work
19.10.2017 | Julius-Maximilians-Universität Würzburg
Rapid environmental change makes species more vulnerable to extinction
19.10.2017 | Universität Zürich
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
17.10.2017 | Event News
10.10.2017 | Event News
10.10.2017 | Event News
19.10.2017 | Materials Sciences
19.10.2017 | Materials Sciences
19.10.2017 | Physics and Astronomy