PDBsum entry 4gj2

Transferase/transferase inhibitor

PDB id: 4gj2

Contents

Protein chain

288 a.a.

Ligands

0XH

Waters ×94

PDB id:

4gj2

Name:

Transferase/transferase inhibitor

Title:

Tyk2 (jh1) in complex with 2,6-dichloro-n-[2-({[(1r,2r)-2- fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide

Structure:

Non-receptor tyrosine-protein kinase tyk2. Chain: a. Fragment: kinase domain, unp residues 696-1022. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tyk2 gene. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.40Å R-factor: 0.198 R-free: 0.237

Authors:

M.H.Ultsch

Key ref:

J.Liang et al. (2013). Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors. J Med Chem, 56, 4521-4536. PubMed id: 23668484 DOI: 10.1021/jm400266t

Date:

09-Aug-12 Release date: 29-May-13

Protein chain

P29597  (TYK2_HUMAN) -  Non-receptor tyrosine-protein kinase TYK2 from Homo sapiens

Seq: 1187 a.a.

Struc: 288 a.a.*

* PDB and UniProt seqs differ at 7 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/jm400266t

J Med Chem 56:4521-4536 (2013)

PubMed id: 23668484

Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors.

J.Liang, A.van Abbema, M.Balazs, K.Barrett, L.Berezhkovsky, W.Blair, C.Chang, D.Delarosa, J.DeVoss, J.Driscoll, C.Eigenbrot, N.Ghilardi, P.Gibbons, J.Halladay, A.Johnson, P.B.Kohli, Y.Lai, Y.Liu, J.Lyssikatos, P.Mantik, K.Menghrajani, J.Murray, I.Peng, A.Sambrone, S.Shia, Y.Shin, J.Smith, S.Sohn, V.Tsui, M.Ultsch, L.C.Wu, Y.Xiao, W.Yang, J.Young, B.Zhang, B.Y.Zhu, S.Magnuson.

ABSTRACT

Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.