EMD-21688
Structure of human TRPA1 in complex with inhibitor GDC-0334
EMD-21688
Single-particle3.6 Å
Deposition: 11/04/2020Map released: 17/02/2021
Last modified: 29/05/2024
Sample Organism:
Homo sapiens
Sample: TRPA1 bound by inhibitor GDC-0334
Fitted models: 6wj5 (Avg. Q-score: 0.471)
Deposition Authors: Rohou A, Rouge L, Arthur CP
Sample: TRPA1 bound by inhibitor GDC-0334
Fitted models: 6wj5 (Avg. Q-score: 0.471)
Deposition Authors: Rohou A, Rouge L, Arthur CP
A TRPA1 inhibitor suppresses neurogenic inflammation and airway contraction for asthma treatment.
Balestrini A,
Joseph V,
Dourado M,
Reese RM 
,
Shields SD,
Rouge L,
Bravo DD ,
Chernov-Rogan T,
Austin CD,
Chen H,
Wang L,
Villemure E,
Shore DGM,
Verma VA,
Hu B,
Chen Y,
Leong L,
Bjornson C,
Hotzel K,
Gogineni A,
Lee WP,
Suto E,
Wu X,
Liu J,
Zhang J,
Gandham V,
Wang J,
Payandeh J,
Ciferri C,
Estevez A ,
Arthur CP,
Kortmann J,
Wong RL ,
Heredia JE,
Doerr J,
Jung M,
Vander Heiden JA,
Roose-Girma M,
Tam L,
Barck KH,
Carano RAD,
Ding HT,
Brillantes B,
Tam C,
Yang X,
Gao SS,
Ly JQ,
Liu L,
Chen L,
Liederer BM,
Lin JH,
Magnuson S,
Chen J,
Hackos DH,
Elstrott J,
Rohou A,
Safina BS,
Volgraf M,
Bauer RN,
Riol-Blanco L
(2021) J Exp Med , 218
,
Shields SD,
Rouge L,
Bravo DD ,
Chernov-Rogan T,
Austin CD,
Chen H,
Wang L,
Villemure E,
Shore DGM,
Verma VA,
Hu B,
Chen Y,
Leong L,
Bjornson C,
Hotzel K,
Gogineni A,
Lee WP,
Suto E,
Wu X,
Liu J,
Zhang J,
Gandham V,
Wang J,
Payandeh J,
Ciferri C,
Estevez A ,
Arthur CP,
Kortmann J,
Wong RL ,
Heredia JE,
Doerr J,
Jung M,
Vander Heiden JA,
Roose-Girma M,
Tam L,
Barck KH,
Carano RAD,
Ding HT,
Brillantes B,
Tam C,
Yang X,
Gao SS,
Ly JQ,
Liu L,
Chen L,
Liederer BM,
Lin JH,
Magnuson S,
Chen J,
Hackos DH,
Elstrott J,
Rohou A,
Safina BS,
Volgraf M,
Bauer RN,
Riol-Blanco L
(2021) J Exp Med , 218
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.
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.