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Drug Design

Xenon and Genentech Publish in Science the 3-D Crystal Structure of a Novel Nav1.7 Compound Binding Site Enabling the Development of Potent Selective Inhibitors to Treat Pain

Burnaby, BC -- Xenon Pharmaceuticals Inc. a clinical-stage biopharmaceutical company, announced publication of a key article in Science by researchers at Xenon and Genentech describing for the first time the X-ray crystal structure of a pharmacological binding site on the Nav1.7 sodium channel allowing for the rational drug design of highly selective inhibitors. Nav1.7 is a member of the voltage-gated ion channel super-family and is a genetically validated target for treating inflammatory and neuropathic pain. These channels open ion-selective pores in response to sensed changes in membrane voltage and stimulate the generation of a response in nerve cells.

Using its Extreme Genetics™ platform, Xenon identified Nav1.7 as a drug target for pain after discovering that the Nav1.7 protein is deficient in the rare genetic disorder congenital indifference to pain, in which people are unable to feel pain. Nav1.7 appears to be essential for pain signaling and based on the significant human validation was selected by Xenon as a key target for the development of novel analgesics.

Since 2011, Xenon and Genentech have been collaborating to discover and develop innovative selective oral inhibitors of Nav1.7 for the treatment of pain. The Science publication, titled “Structural Basis of Nav1.7 Inhibition by a Selective Small Molecule Antagonist,” by Ahuja et al. describes for the first time the use of X-ray crystallography and protein engineering to describe at the molecular level a new receptor site within a Nav1.7 voltage sensor potentially enabling the development of highly selective small molecule inhibitors. The authors believe that this discovery establishes a structural blueprint for designing other selective Nav channel inhibitors for treating pain and other diseases.

Morgan Sheng, M.B.B.S., Ph.D., Vice President, Neuroscience at Genentech, said, “This important discovery reported in Science has the potential to accelerate the development of potentially breakthrough treatments for pain. We believe that our studies characterize the mechanism of an important new class of compounds that possess both functional and molecular selectivity, which is previously unknown among small molecule ligands of the Nav channel family.”

Dr. Simon Pimstone, Xenon’s President and Chief Executive Officer, said, “We believe that this publication provides additional validation for Xenon’s Extreme Genetics discovery platform, which enables us to leverage unique insights into human genetics to identify single genes associated with rare phenotypes that can represent important new targets for intractable diseases. We are excited by the progress we are making in our pain-focused strategic alliances with Genentech. Furthermore, we believe that the elucidation of the X-ray structure and novel binding site on Nav1.7 could also enhance Xenon’s ability to discover novel molecules targeting other voltage gated ion channel programs.”

Genentech is developing two novel Nav1.7 small-molecule inhibitors for pain, GDC-0276 and GDC-0310, which are both currently in Phase I clinical trials. These compounds are both highly potent and selective inhibitors of Nav1.7.

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