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.”