A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment PMID: 33620419

ADC Targets in Oncology

2026-04-10

A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment

J Exp Med. 2021 Apr 5;218(4):e20201637. doi: 10.1084/jem.20201637.

Alessia Balestrini ¹ , Victory Joseph ² , Michelle Dourado ³ , Rebecca M Reese ³ , Shannon D Shields ³ , Lionel Rougé ⁴ , Daniel D Bravo ⁵ , Tania Chernov-Rogan ⁵ , Cary D Austin ⁶ , Huifen Chen ⁷ , Lan Wang ⁷ , Elisia Villemure ⁷ , Daniel G M Shore ⁷ , Vishal A Verma ⁷ , Baihua Hu ⁸ , Yong Chen ⁸ , Laurie Leong ⁶ , Chris Bjornson ⁶ , Kathy Hötzel ⁶ , Alvin Gogineni ² , Wyne P Lee ⁹ , Eric Suto ⁹ , Xiumin Wu ⁹ , John Liu ⁹ , Juan Zhang ⁹ , Vineela Gandham ² , Jianyong Wang ⁵ , Jian Payandeh ⁴ , Claudio Ciferri ⁴ , Alberto Estevez ⁴ , Christopher P Arthur ⁴ , Jens Kortmann ¹ , Ryan L Wong ¹ , Jose E Heredia ¹ , Jonas Doerr ¹⁰ , Min Jung ¹¹ , Jason A Vander Heiden ¹¹ , Merone Roose-Girma ¹⁰ , Lucinda Tam ¹⁰ , Kai H Barck ² , Richard A D Carano ² , Han Ting Ding ¹² , Bobby Brillantes ¹³ , Christine Tam ¹³ , Xiaoying Yang ¹⁴ , Simon S Gao ¹⁵ , Justin Q Ly ¹⁶ , Liling Liu ¹⁶ , Liuxi Chen ¹⁶ , Bianca M Liederer ¹⁶ , Joseph H Lin ¹⁷ , Steven Magnuson ⁷ , Jun Chen ⁵ , David H Hackos ³ , Justin Elstrott ² , Alexis Rohou ⁴ , Brian S Safina ⁷ , Matthew Volgraf ⁷ , Rebecca N Bauer ¹⁸ , Lorena Riol-Blanco ¹

Affiliations

1. Department of Immunology Discovery, Genentech, Inc., South San Francisco, CA.
2. Department of Biomedical Imaging, Genentech, Inc., South San Francisco, CA.
3. Department of Neuroscience, Genentech, Inc., South San Francisco, CA.
4. Department of Structural Biology, Genentech, Inc., South San Francisco, CA.
5. Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, CA.
6. Department of Pathology, Genentech, Inc., South San Francisco, CA.
7. Department of Discovery Chemistry, Genentech, Inc., South San Francisco, CA.
8. Pharmaron-Beijing Co. Ltd., BDA, Beijing, People's Republic of China.
9. Department of Translational Immunology, Genentech, Inc., South San Francisco, CA.
10. Department of Molecular Biology, Genentech, Inc., South San Francisco, CA.
11. Department of OMNI Bioinformatics, Genentech, Inc., South San Francisco, CA.
12. Department of Clinical Pharmacology, Genentech, Inc., South San Francisco, CA.
13. Department of Biomolecular Resources, Genentech, Inc., South San Francisco, CA.
14. Department of Product Development Biometric Biostatistics, Genentech, Inc., South San Francisco, CA.
15. Department of Clinical Imaging, Genentech, Inc., South San Francisco, CA.
16. Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA.
17. Department of Early Clinical Development, Genentech, Inc., South San Francisco, CA.
18. Department of OMNI-Biomarker Development, Genentech, Inc., South San Francisco, CA.

Abstract

Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.