Advancing chemical genomics: NIH selects Odyssey Thera screening technology

SAN RAMON, Calif.—Biomolecular technology and pharmaceutical company Odyssey Thera announced recently it had signed an agreement to provide the NIH Chemical Genomics Center (NCGC) with a cell-based compound screening system that will be used to further the NIH Molecular Libraries Roadmap Initiative. The technology, protein-fragment complementation assay (PCA), will allow NCGC to screen human cell lines for the impact of potential drugs on biochemical pathways. Financial terms of the agreement were not disclosed.

"I have been following the development of PCA technology since the mid-90s and have been impressed by the method's ability to delimitthe steps of complex cellular pathways," says Dr. James Inglese, NCGC Deputy Director. "The NCGC is interested in identifying assay technologies that may be of use and interest to the Molecular Libraries Screening Center Network (MLSCN) and its academic collaborators."

Ultimately, the data derived from the PCA-based screening experiments will be entered into the publicly accessible PubChem database, as with all Roadmap data. However, Odyssey Thera has the right to review the results beforehand, which may lead to licensing opportunities for the pharmaceutical firm and potentially expand the company's preclinical programs focused in oncology, with novel small molecules with activity against validated targets and pathways.

The NCGC is very interested in discovering small-molecule modulators for proteins of unknown function that may be operating in important signaling pathways, and in modulating the dynamics of protein-protein interactions within such pathways and networks, he adds. PCA has the potential to aid in this search.

"This is a scientific collaboration where Odyssey is supplying specifically engineered PCA cell lines, protocols, and scientific know-how, and the NCGC is optimizing the assay for 1536-well screening and detection using a laser scanning imaging system," Inglese says.

According to Dr. Marnie Mac-Donald, president and CEO of Odyssey Thera, PCA will allow NCGC scientists to test their libraries of compounds under more realistic conditions.

"All of the synthetic chemical probes and drugs that exist today were identified in a test tube, using an isolated protein target," she explains. "But in real life, drugs act within the complex biological systems of the body and the intricate networks of human cells. These networks are made up of dynamic, physical interactions of proteins that are organized in pathways."

Says MacDonald, you can measure these interactions with PCA, within pathways of interest, directly in human cells and in real time. When an interaction occurs, a very bright fluorescence signal is generated at the site of the interaction. If a small molecule probe or drug turns on or turns off a particular pathway, the fluorescence signal increases or decreases, and this can be measured very precisely with state-of-the-art instrumentation.

This agreement is just the latest in a growing trend of companies and organizations moving to cell-based assay systems, a market that is steadily approaching $1 billion per year and double-digit growth by some estimates.

"Cell-based assays open up access to proteins and protein complexes not easily isolated in a purified form and for those whose activity is modulated by the cellular environment in a way not reproduced in a cell-free system," Inglese says.

"Out of the thousands of potential drug targets in the cell, only a small fraction can be assayed with in vitro methods today, so we are all missing a lot of gold when it comes to discovering new drugs," adds MacDonald. "With cell-based assays, you can screen against otherwise 'un-druggable' targets."

Furthermore, she argues, with in vitro assays, you find compounds that are potent and have the right chemical properties. But when the so-called targeted compound gets into a cell, it takes on a life of its own and can bind to many other molecules, which leads to unintended off-target effects.

"If you know about these effects at the hit-to-lead stage you can save costs by avoiding blind alleys, and you can use the information to optimize your leads and remove compounds that are nonselective in cells," she adds.