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!
Less animal experiments on the horizon: Multi-organ chip awarded
19.10.2018 | Fraunhofer-Institut für Werkstoff- und Strahltechnik IWS
RUDN chemist tested a new nanocatalyst for obtaining hydrogen
18.10.2018 | RUDN University
Scientists at the Max Planck Institute for Polymer Research (MPI-P) in Mainz (Germany) together with scientists from Dresden, Leipzig, Sofia (Bulgaria) and Madrid (Spain) have now developed and characterized a novel, metal-organic material which displays electrical properties mimicking those of highly crystalline silicon. The material which can easily be fabricated at room temperature could serve as a replacement for expensive conventional inorganic materials used in optoelectronics.
Silicon, a so called semiconductor, is currently widely employed for the development of components such as solar cells, LEDs or computer chips. High purity...
Augsburg chemists present a new technology for compressing, storing and transporting highly volatile gases in porous frameworks/New prospects for gas-powered vehicles
Storage of highly volatile gases has always been a major technological challenge, not least for use in the automotive sector, for, for example, methane or...
When we put water in a freezer, water molecules crystallize and form ice. This change from one phase of matter to another is called a phase transition. While this transition, and countless others that occur in nature, typically takes place at the same fixed conditions, such as the freezing point, one can ask how it can be influenced in a controlled way.
We are all familiar with such control of the freezing transition, as it is an essential ingredient in the art of making a sorbet or a slushy. To make a cold...
Thin organic layers provide machines and equipment with new functions. They enable, for example, tiny energy recuperators. In future, these will be installed...
Das Zusammenspiel aus Struktur und Dynamik bestimmt die Funktion von Proteinen, den molekularen Werkzeugen der Zelle. Durch Fortschritte in der...
17.10.2018 | Event News
16.10.2018 | Event News
02.10.2018 | Event News
19.10.2018 | Earth Sciences
19.10.2018 | Life Sciences
19.10.2018 | Health and Medicine