COU RT ESY O F G IDEO N BO L L AG
NEWS OF THE WEEK
HOPE FOR MELANOMA REVEALED DRUG DEVELOPMENT: Promising skin cancer therapy targets a rogue kinase
T
HE STRUCTURE of a kinase enzyme inhibitor
that could become a next-generation drug for melanoma made its public debut last week (Nature, DOI: 10.1038/nature09454). The unveiling comes on the heels of highly successful results in an early-stage clinical trial of the drug that support the idea that targeted therapies can be effective strategies against cancers. Inspired by Gleevec, the celebrated drug that treats Raf—is nearly always in that active state, Bollag says. certain types of leukemia by targeting a specific kinase Although PLX4032 was potent, little of it reached enzyme, many companies are trying to develop therathe bloodstream in its initial crystalline formulation. pies by blocking other rogue kinases thought to be at the So researchers at pharmaceutical company Roche, root of some cancers. A team at Berkeley, Calif., start-up which is codeveloping the compound with Plexxikon, Plexxikon has focused on the kinase B-Raf, a culprit in developed an amorphous formulation instead. Among metastatic melanoma, the deadliest form of skin cancer. melanoma patients who received the newly formulated “About half of all melanomas have a specific mutation PLX4032 pills, 81% saw their tumors shrink, a response in the B-Raf gene,” says biochemist Gideon Bollag, team rate usually unheard of for an intractable cancer. leader and senior vice president of research at Plexxikon. Late-stage clinical trials of PLX4032 are under way. “We reasoned that we could test However, the compound works F whether it would be a good target only in melanoma patients with O Cl for melanoma patients.” the B-Raf mutation, and many O To discover the experimenof the patients’ tumors eventuN S tal drug PLX4032, Plexxikon’s ally developed resistance to the F H scientists screened for small medication. “We’d like to find O N N scaffolds that bound weakly out how resistance happens in PLX4032 to the B-Raf mutant, and then, the cell so we can make the treatwith help from X-ray crystallography, decorated that ment more effective,” Bollag says. scaffold core to make a potent B-Raf inhibitor. Crystal “The remarkable efficacy of PLX4032 and the comstructures suggest that PLX4032 binds near a regulaplete correspondence between response and mutation of tory loop on the kinase, but only when the loop is in B-Raf is the second example, after Gleevec, of the amazits active configuration. “We think the fact that the ing efficacy achievable by targeting mutant activated kicompound binds only to the active form explains its nases,” says Kevan M. Shokat, a kinase expert at the Uniselectivity,” because mutant B-Raf—but not normal B- versity of California, San Francisco.—CARMEN DRAHL
Plexxikon’s inhibitor (mostly green, structure shown below) makes contacts with an important loop in B-Raf (mostly yellow).
MERGERS AND ACQUISITIONS Airgas rejection sets stage for a showdown Airgas has once again declined a sweetened takeover offer from Air Products & Chemicals. With Airgas’ board of directors refusing to negotiate, the annual meeting of the company’s shareholders later this week promises to be the climax of the takeover drama, after which Air Products is threatening to walk away from the deal. Air Products’ new offer is $65.50 per share. In February, the company launched a hostile takeover of Airgas for $60.00 per share. In July, it raised its bid to $63.50. Airgas CEO Peter McCausland repeated
his argument against Air Products’ entreaties in rejecting the latest offer, saying it “continues to grossly undervalue Airgas.” At Airgas’ annual meeting, scheduled for Sept. 15, Air Products will try to get elected three directors it has nominated to the Airgas board and force Airgas to hold its next shareholders’ meeting in January, rather than in June as it currently plans. “If Airgas shareholders do not elect these three nominees and approve all of our proposals, we will conclude that shareholders do not want a sale of Airgas
WWW.CEN-ONLINE.ORG
7
SEPTEMBER 13, 2010
at this time—and we will therefore terminate our offer and move on,” Air Products CEO John E. McGlade says. Airgas has promised its shareholders that it will “explore all available alternatives” to the offer if they reject Air Products’ proposal to push the next meeting up to January. “In this regard, the Airgas board has made clear on numerous occasions its willingness to engage in negotiations that it believed would result in appropriate value for Airgas stockholders,” the company says.—ALEX TULLO
