PDBsum entry 5f1z

Transferase/transferase inhibitor

PDB id: 5f1z

Contents

Protein chain

281 a.a.

Ligands

5U3

Waters ×155

PDB id:

5f1z

Name:

Transferase/transferase inhibitor

Title:

Structure of tyk2 with inhibitor 16: 3-azanyl-5-[(2~{s})-3- methylbutan-2-yl]-7-[1-methyl-5-(2-oxidanylpropan-2-yl)pyrazol-3-yl]- 1~{h}-pyrazolo[4,3-c]pyridin-4-one

Structure:

Non-receptor tyrosine-protein kinase tyk2. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tyk2. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469

Resolution:

2.65Å R-factor: 0.220 R-free: 0.310

Authors:

R.J.Skene

Key ref:

T.Yogo et al. (2016). Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors. J Med Chem, 59, 733-749. PubMed id: 26701356 DOI: 10.1021/acs.jmedchem.5b01857

Date:

01-Dec-15 Release date: 13-Jan-16

Protein chain

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

Seq: 1187 a.a.

Struc: 281 a.a.*

* PDB and UniProt seqs differ at 3 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/acs.jmedchem.5b01857

J Med Chem 59:733-749 (2016)

PubMed id: 26701356

Structure-Based Design and Synthesis of 3-Amino-1,5-dihydro-4H-pyrazolopyridin-4-one Derivatives as Tyrosine Kinase 2 Inhibitors.

T.Yogo, H.Nagamiya, M.Seto, S.Sasaki, H.Shih-Chung, Y.Ohba, N.Tokunaga, G.N.Lee, C.Y.Rhim, C.H.Yoon, S.Y.Cho, R.Skene, S.Yamamoto, Y.Satou, M.Kuno, T.Miyazaki, H.Nakagawa, A.Okabe, S.Marui, K.Aso, M.Yoshida.

ABSTRACT

We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1-3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of 20. Compound 20 inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor.