Melanoma Drug's Structure Revealed

Courtesy of Gideon Bollag

IN THE LOOP Plexxikon's inhibitor (mostly green) makes contacts with an important loop in B-Raf (mostly yellow).

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medicinal chemistry, structural biology, cancer, kinase

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The structure of a kinase enzyme inhibitor that could become a next-generation drug for melanoma made its public debut this 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, which support the idea that targeted therapies can be effective strategies against cancers.

Inspired by Gleevec, the celebrated drug that treats certain types of leukemia by targeting a specific kinase enzyme, many companies are trying to develop therapies by blocking other rogue kinases thought to be at some cancers' roots. A team at Berkeley, Calif., start-up Plexxikon has focused on the kinase B-Raf, a culprit in metastatic melanoma, the deadliest form of skin cancer. "About half of all melanomas have a specific mutation in the B-Raf gene," says biochemist Gideon Bollag, senior vice president of research at Plexxikon, who led the team. "We reasoned we could test whether it would be a good target for melanoma patients."

To discover the experimental drug PLX4032, Plexxikon's scientists screened for small "scaffolds" that bound weakly to the B-Raf mutant, and then, with help from X-ray crystallography, decorated that scaffold core to make a potent B-Raf inhibitor. Crystal structures suggest that PLX4032 binds near a regulatory loop on the kinase, but only when the loop is in its active configuration. "We think the fact that the compound binds only to the active form explains its selectivity," because mutant B-Raf—but not normal B-Raf—is nearly always in that active state, Bollag says.

Although PLX4032 was potent, little of it reached the bloodstream in its initial crystalline formulation. So researchers at pharmaceutical company Roche, which is codeveloping the compound with Plexxikon, developed an amorphous formulation instead. Among melanoma patients who received the newly formulated PLX4032 pills, 81% saw their tumors shrink, a response rate usually unheard of for an intractable cancer.

Late-stage clinical trials of PLX4032 are under way. However, the compound only works in melanoma patients with the B-Raf mutation, and many of the patients' tumors eventually developed resistance to the medication. "We'd like to find out how resistance happens in the cell so we can make the treatment more effective," Bollag says. PLX4032 could also be used in drug combinations, he says.

"The remarkable efficacy of PLX4032 and the complete correspondence between response and mutation of B-Raf is the second example, after Gleevec, of the amazing efficacy achievable by targeting mutant activated kinases," says Kevan M. Shokat, a kinase expert at the University of California, San Francisco.

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Copyright © 2011 American Chemical Society