8S99

Crystal structure of the TYK2 pseudokinase domain in complex with compound 11

Summary for 8S99

• Entry DOI: 10.2210/pdb8s99/pdb
• Descriptor: Non-receptor tyrosine-protein kinase TYK2, (8S)-N-[(1R,2S)-2-fluorocyclopropyl]-5-{[(1M,2'M)-3'-fluoro-2-oxo-2H-[1,2'-bipyridin]-3-yl]amino}-7-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: tyk2, pseudokinase, jh2, immunology, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 100872.11

Authors

Toms, A.V.,Leit, S.,Greenwood, J.R.,Carriero, S.,Mondal, S.,Abel, R.,Ashwell, M.,Blanchette, H.,Boyles, N.,Cartwright, M.,Collis, A.,Feng, S.,Ghanakota, P.,Harriman, G.C.,Hosagrahara, V.,Kaila, N.,Kapeller, R.,Rafi, S.,Romero, D.L.,Tarantino, P.,Timaniya, J.,Wester, R.T.,Westlin, W.,Srivastava, B.,Miao, W.,Tummino, P.,McElwee, J.J.,Edmondson, S.D.,Massee, C.E. (deposition date: 2023-03-27, release date: 2023-07-26, Last modification date: 2023-08-23)

Primary citation

Leit, S.,Greenwood, J.,Carriero, S.,Mondal, S.,Abel, R.,Ashwell, M.,Blanchette, H.,Boyles, N.A.,Cartwright, M.,Collis, A.,Feng, S.,Ghanakota, P.,Harriman, G.C.,Hosagrahara, V.,Kaila, N.,Kapeller, R.,Rafi, S.B.,Romero, D.L.,Tarantino, P.M.,Timaniya, J.,Toms, A.V.,Wester, R.T.,Westlin, W.,Srivastava, B.,Miao, W.,Tummino, P.,McElwee, J.J.,Edmondson, S.D.,Masse, C.E.
Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.
J.Med.Chem., 66:10473-10496, 2023

PubMed Abstract: TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, and these cytokines have been implicated in the pathogenesis of multiple inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, and inflammatory bowel diseases. Supported by compelling data from human genome-wide association studies and clinical results, TYK2 inhibition through small molecules is an attractive therapeutic strategy to treat these diseases. Herein, we report the discovery of a series of highly selective pseudokinase (Janus homology 2, JH2) domain inhibitors of TYK2 enzymatic activity. A computationally enabled design strategy, including the use of FEP+, was instrumental in identifying a pyrazolo-pyrimidine core. We highlight the utility of computational physics-based predictions used to optimize this series of molecules to identify the development candidate , a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.

PubMed: 37427891
DOI: 10.1021/acs.jmedchem.3c00600

Experimental method

X-RAY DIFFRACTION (1.71 Å)