| Structural highlights
Disease
TYK2_HUMAN Mendelian susceptibility to mycobacterial diseases;Autosomal recessive hyper IgE syndrome. Defects in TYK2 are the cause of protein-tyrosine kinase 2 deficiency (TYK2 deficiency) [MIM:611521; also known as autosomal recessive hyper-IgE syndrome (HIES) with atypical mycobacteriosis. TYK2 deficiency consists of a primary immunodeficiency characterized by recurrent skin abscesses, pneumonia, and highly elevated serum IgE.
Function
TYK2_HUMAN Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.[1]
Publication Abstract from PubMed
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 30, a potent, exquisitely selective cellular TYK2 inhibitor that is currently in Phase 2 clinical trials for the treatment of psoriasis and psoriatic arthritis.
Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279.,Leit S, Greenwood J, Carriero S, Mondal S, Abel R, Ashwell M, Blanchette H, Boyles NA, Cartwright M, Collis A, Feng S, Ghanakota P, Harriman GC, Hosagrahara V, Kaila N, Kapeller R, Rafi SB, Romero DL, Tarantino PM, Timaniya J, Toms AV, Wester RT, Westlin W, Srivastava B, Miao W, Tummino P, McElwee JJ, Edmondson SD, Masse CE J Med Chem. 2023 Jul 10. doi: 10.1021/acs.jmedchem.3c00600. PMID:37427891[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol. 1994 Dec;14(12):8133-42. PMID:7526154
- ↑ Leit S, Greenwood J, Carriero S, Mondal S, Abel R, Ashwell M, Blanchette H, Boyles NA, Cartwright M, Collis A, Feng S, Ghanakota P, Harriman GC, Hosagrahara V, Kaila N, Kapeller R, Rafi SB, Romero DL, Tarantino PM, Timaniya J, Toms AV, Wester RT, Westlin W, Srivastava B, Miao W, Tummino P, McElwee JJ, Edmondson SD, Masse CE. Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279. J Med Chem. 2023 Jul 10. PMID:37427891 doi:10.1021/acs.jmedchem.3c00600
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