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
Herein we report an efficient method for the synthesis of a highly functionalized 2-pyrrolidinone, tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylate, from readily available starting materials. Utility of this compound was demonstrated in the synthesis of a novel series of macrocyclic Tyk2 inhibitors, leading to the identification of a potent and selective macrocyclic Tyk2 inhibitor (26).
Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors.,Sasaki Y, Tokuhara H, Ohba Y, Okabe A, Nakayama M, Nakagawa H, Skene R, Hoffman I, Zou H, Yoshida M Bioorg Med Chem Lett. 2020 Mar 1;30(5):126963. doi: 10.1016/j.bmcl.2020.126963., Epub 2020 Jan 13. PMID:31980341[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
- ↑ Sasaki Y, Tokuhara H, Ohba Y, Okabe A, Nakayama M, Nakagawa H, Skene R, Hoffman I, Zou H, Yoshida M. Efficient synthesis of tert-butyl 3-cyano-3-cyclopropyl-2-oxopyrrolidine-4-carboxylates: Highly functionalized 2-pyrrolidinone enabling access to novel macrocyclic Tyk2 inhibitors. Bioorg Med Chem Lett. 2020 Mar 1;30(5):126963. doi: 10.1016/j.bmcl.2020.126963., Epub 2020 Jan 13. PMID:31980341 doi:http://dx.doi.org/10.1016/j.bmcl.2020.126963
