PerspectiveCell Biology

The Unusual Case of Porcupine

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Science  24 Aug 2012:
Vol. 337, Issue 6097, pp. 922-923
DOI: 10.1126/science.1228179

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Earlier this year, with little fanfare, one of the first small molecules targeting Wnt-mediated cellular signaling, called LGK974, entered a phase I clinical trial. Cell signaling that is controlled by secreted Wnt proteins is pivotal in animal development and tissue homeostasis, and has become a high-priority anticancer drug target given its essential role in colorectal cancer and its contribution to a broad range of other cancer types (1, 2). The importance of targeting this pathway was recently highlighted in a keynote address by Harold Varmus at a meeting in the Netherlands (3) marking the 30th anniversary of the discovery of the first Wnt molecule (there are 19 of them). With Roel Nusse, Varmus linked deviant activity of Wnt molecules to cancer. Although the target of LGK974—an acyltransferase called Porcupine (Porcn) that adds fatty acid to Wnt—has been well studied, few of the meeting participants were aware of the drug candidate, reflecting the remarkable speed and circumstances whereby this compound was nominated as a clinical candidate. The atypical path to the discovery of LGK974 may also signal changes in the approach to cancer drug discovery that include an increasing reliance on collaboration between government and industry to bring new drug targets to clinical testing.