SAN DIEGO—Pharmaceutical companies Ambit Biosciences and Cephalon recently an-nounced the signing of a screening, discovery and development agreement that will see the companies tackle kinases, key molecules in many disease pathways. Working on two undisclosed kinase targets, Ambit will discover and deliver lead compounds, which Cephalon will pursue for preclinical and clinical development as well as commercialization.
For their services, Ambit will receive $18 million upfront and potential milestone payments up to $232.5 million, as well as royalties on the sales of any products arising from the collaboration.
"Kinase inhibition as a mechanism for novel therapeutics is complex, extremely challenging from the aspect of finding a druggable chemotype and information-intensive," says Dr. Jeffrey Vaught, Cephalon executive VP of R&D. "We recognized very early that a strategic alliance with a kinome-centric organization would compliment and strengthen our internal capabilities.
"After evaluating several technologies, we felt that Ambit had several important attributes that included: world-class technology, a scientific and management team that understood and were committed to drug discovery and an impressive track record of accomplishment."
According to Dr. Shripad Bhagwat, Ambit senior VP of drug discovery, Ambit will also screen Cephalon's kinase-focused library using KinomeScan to select novel leads for multiple undisclosed kinase targets of interest to Ambit. The company retains rights to pursue these leads independently to discover kinase inhibitor drugs.
Ambit's screening platform, KinomeScan, works by directly and quantitatively measuring competitive binding of small molecules to the ATP binding site of kinases. What sets the system apart, says Dr. Patrick Zarrinkar, Ambit senior director of technology development and alliance management, is the ability to screen compounds on a massively parallel scale and under identical conditions. For example, 10,000 compounds can be screened against a panel of approximately 300 kinases, yielding 3,000,000 data points in months rather than years.
"We are entering an era in kinase research which is very similar to that with GPCRs where the breadth of potential interaction of the compound can dictate, not only efficacy, but potential unwanted off-target activities and toxicity," Vaught says. "KinomeScan offers real-time data back to the synthesizing chemist to inform his/her next synthesis."
One of the challenges in developing kinase inhibitors is the ubiquity of the proteins throughout the human proteome—some estimates suggest as many as 500 different kinases—and their pivotal role as a primary point-of-entry for many biological pathways. At present, KinomeScan includes 300 kinases.
"The representation of kinase subfamilies in Ambit's panel is comparable to their representation in the human kinome as a whole," Zarrinkar says. "Ambit's panel will continue to grow, and we anticipate that within two to three years the panel will contain the vast majority, if not all, human protein kinases."
From Vaught's perspective, however, the distribution of kinases may actually be a blessing rather than a curse.
"While there is a lot of discussion around kinase inhibitor selectivity, I am much more interested in the potential ability to specifically target multiple mechanisms, built into a single compound, which pharmacologically can be demonstrated to be complimentary, important to the pathology of disease and synergistic when combined," he says. "This would be and is impossible without a full panel of data from which to instruct and guide the synthesizing chemist."