8TB5

TYK2 JH2 bound to Compound7

Summary for 8TB5

• Entry DOI: 10.2210/pdb8tb5/pdb
• Descriptor: Non-receptor tyrosine-protein kinase TYK2, ACETATE ION, N-{(3P)-3-[3-(dimethylsulfamoyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-5-yl}cyclopropanecarboxamide, ... (4 entities in total)
• Functional Keywords: tyk2, pseudokinase, azaindole, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 73873.59

Authors

Argiriadi, M.A.,Van Epps, S.A.,Breinlinger, E.C. (deposition date: 2023-06-28, release date: 2023-10-18, Last modification date: 2023-11-08)

Primary citation

Breinlinger, E.,Van Epps, S.,Friedman, M.,Argiriadi, M.,Chien, E.,Chhor, G.,Cowart, M.,Dunstan, T.,Graff, C.,Hardee, D.,Herold, J.M.,Little, A.,McCarthy, R.,Parmentier, J.,Perham, M.,Qiu, W.,Schrimpf, M.,Vargo, T.,Webster, M.P.,Wu, F.,Bennett, D.,Edmunds, J.
Targeting the Tyrosine Kinase 2 (TYK2) Pseudokinase Domain: Discovery of the Selective TYK2 Inhibitor ABBV-712.
J.Med.Chem., 66:14335-14356, 2023

PubMed Abstract: Tyrosine kinase 2 (TYK2) is a nonreceptor tyrosine kinase that belongs to the JAK family also comprising JAK1, JAK2, and JAK3. TYK2 is an attractive target for various autoimmune diseases as it regulates signal transduction downstream of IL-23 and IL-12 receptors. Selective TYK2 inhibition offers a differentiated clinical profile compared to currently approved JAK inhibitors. However, selectivity for TYK2 versus other JAK family members has been difficult to achieve with small molecules that inhibit the catalytically active kinase domain. Successful targeting of the TYK2 pseudokinase domain as a strategy to achieve isoform selectivity was recently exemplified with deucravacitinib. Described herein is the optimization of selective TYK2 inhibitors targeting the pseudokinase domain, resulting in the discovery of the clinical candidate ABBV-712 ().

PubMed: 37823891
DOI: 10.1021/acs.jmedchem.3c01373

Experimental method

X-RAY DIFFRACTION (2.32 Å)