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

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.

• Authors: Alessia Balestrini, Victory Joseph, Michelle Dourado, Rebecca M Reese, Shannon D Shields, Lionel Rougé, Daniel D Bravo, Tania Chernov-Rogan, Cary D Austin, Huifen Chen, Lan Wang, Elisia Villemure, Daniel G M Shore, Vishal A Verma, Baihua Hu, Yong Chen, Laurie Leong, Chris Bjornson, Kathy Hötzel, Alvin Gogineni, Wyne P Lee, Eric Suto, Xiumin Wu, John Liu, Juan Zhang, Vineela Gandham, Jianyong Wang, Jian Payandeh, Claudio Ciferri, Alberto Estevez, Christopher P Arthur, Jens Kortmann, Ryan L Wong, Jose E Heredia, Jonas Doerr, Min Jung, Jason A Vander Heiden, Merone Roose-Girma, Lucinda Tam, Kai H Barck, Richard A D Carano, Han Ting Ding, Bobby Brillantes, Christine Tam, Xiaoying Yang, Simon S Gao, Justin Q Ly, Liling Liu, Liuxi Chen, Bianca M Liederer, Joseph H Lin, Steven Magnuson, Jun Chen, David H Hackos, Justin Elstrott, Alexis Rohou, Brian S Safina, Matthew Volgraf, Rebecca N Bauer, Lorena Riol-Blanco
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 218 Issue 4 (04 05 2021) ISSN: 1540-9538 [Electronic] United States
• PMID: 33620419 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Genentech.

Chemical References

• GDC-0334
• Isothiocyanates
• Pyridines
• Pyrimidines
• TRPA1 Cation Channel
• TRPA1 protein, human
• Trpa1 protein, mouse
• 2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate

Topics

• Adolescent
• Adult
• Animals
• Asthma (drug therapy)
• Cohort Studies
• Disease Models, Animal
• Dogs
• Double-Blind Method
• Female
• Guinea Pigs
• Healthy Volunteers
• Humans
• Isothiocyanates (administration & dosage)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Neurogenic Inflammation (drug therapy)
• Pain (chemically induced, drug therapy)
• Pruritus (chemically induced, drug therapy)
• Pyridines (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• TRPA1 Cation Channel (antagonists & inhibitors, deficiency)
• Treatment Outcome
• Young Adult