BioWorld International Correspondent
LONDON - Astex Therapeutics Ltd. agreed to a deal with AstraZeneca plc for a range of early stage small-molecule kinase inhibitors, securing an up-front payment of $5 million, to be followed by research and development funding, potential milestones of up to $270 million and double-digit royalties.
"This is an excellent deal," Harren Jhoti, Astex's chief scientific officer, told BioWorld International. "Strategically, what it says is that even products that are yet to enter formal preclinical development are assets pharma is prepared to pay significant amounts for. I hope this message will filter through to the financial markets."
The agreement gives AstraZeneca worldwide rights to protein kinase B (PKB) inhibitors that Astex has discovered under an academic collaboration with the Institute of Cancer Research and Cancer Research Technology Ltd., both of London.
"We have identified several series of compounds, all of which are potent inhibitors, and also are active in animal models. We have very nice data and have made good progress," Jhoti said. Cambridge-based Astex's relationship with its academic partners is not affected by the deal with London-based AstraZeneca.
Although he could not give precise details of when the milestones will be triggered, or the number of compounds involved, Jhoti said some payments would be due before AstraZeneca takes over the products for formal preclinical development.
"Considerable work is needed still [on optimization], but I anticipate we will hit some milestones in a matter of months, because the lead compounds are pretty well progressed," he said.
It is Astex's third agreement with AstraZeneca, following deals on cytochrome P450 structures and inhibitors of beta-secretase, an Alzheimer's disease target.
PKB (also known as Akt) is a ser/thr kinase that is activated in tumors following disruption of the tumor suppressor PTEN. It's turned on by many growth factors and has roles in the growth and survival of many tumor types. Significantly for AstraZeneca, up-regulation of PKB is implicated in resistance of tumors to EGFR kinase inhibitors, such as the company's cancer drug Iressa. Up-regulation of the enzyme also is associated with resistance to chemotherapeutics, including doxorubicin and cisplatin, opening up the possibility that PKB inhibitors could be used in both monotherapy and in combination with existing therapies.
Jhoti noted, "It's still a hypothesis at this stage, but data from patients who develop resistance do show up-regulation of PKB, making this an interesting target in terms of multi-therapies."
PKB's potential involvement in resistance to chemotherapies has emerged since Astex began its work on the target. "You work hard and you take your luck, but uncovering a further layer of significance in this target is the icing on the cake," Jhoti said.
Although PKB is a well-known target, it has proved less tractable than other kinases. Astex uses high-throughput X-ray crystallography to characterize drug fragments bound to target proteins and then optimizes those through conventional medicinal chemistry.
"We have been able to make progress against this target when other people haven't been able to. It is a kinase, and there is a general sense that all kinases are the same. But in fact some are so dissimilar that the chemistry required is quite different, and this highlights one of the key advantages of our fragment-based approach," Jhoti said.