molecules of the month


oral TRPA1 ion-channel inhibitor

for asthma, target engagement in HV Ph. I

from ligand-based design, cryo-EM structure

J. Exp. Med., Apr. 5, 2021

Genentech Inc., South San Francisco, CA

1 min read

The Genentech TRPA1 ion-channel inhibitor, GDC-0334, is an oral candidate for asthma that demonstrated target engagement in a non-invasive skin- based Ph. I study. It reduces TRPA1 agonist-induced symptoms in healthy volunteers, with near complete TRPA1 inhibition at 600 mg. TRPA1 is most well-known as a receptor activated by irritants such as allyl isothiocyanate, the irritant in wasabi. Though there has been significant interest in targeting TRPA1 for various conditions including pain, validating the biology preclinically has been challenging due to species expression differences, the possibility of different inhibitor sites of action, and the difficulty in identifying inhibitors with suitable in vivo profiles. The authors describe evaluation of GDC-0334 across multiple developed species models, disclose human data, and characterize the binding mode…

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