PDBsum entry 6bbv

Transferase/transferase inhibitor

PDB id: 6bbv

Contents

Protein chain

289 a.a.

Ligands

D7D

Waters ×172

PDB id:

6bbv

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of jak2 in complex with compound 25

Structure:

Tyrosine-protein kinase jak2. Chain: a. Fragment: protein kinase 2, residues 837-1132. Synonym: janus kinase 2,jak-2. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: jak2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

1.80Å R-factor: 0.178 R-free: 0.215

Authors:

S.Han

Key ref:

M.L.Vazquez et al. (2018). Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases. J Med Chem, 61, 1130-1152. PubMed id: 29298069 DOI: 10.1021/acs.jmedchem.7b01598

Date:

19-Oct-17 Release date: 17-Jan-18

Protein chain

O60674  (JAK2_HUMAN) -  Tyrosine-protein kinase JAK2 from Homo sapiens

Seq: 1132 a.a.

Struc: 289 a.a.*

* PDB and UniProt seqs differ at 2 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.7b01598

J Med Chem 61:1130-1152 (2018)

PubMed id: 29298069

Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases.

M.L.Vazquez, N.Kaila, J.W.Strohbach, J.D.Trzupek, M.F.Brown, M.E.Flanagan, M.J.Mitton-Fry, T.A.Johnson, R.E.TenBrink, E.P.Arnold, A.Basak, S.E.Heasley, S.Kwon, J.Langille, M.D.Parikh, S.H.Griffin, J.M.Casavant, B.A.Duclos, A.E.Fenwick, T.M.Harris, S.Han, N.Caspers, M.E.Dowty, X.Yang, M.E.Banker, M.Hegen, P.T.Symanowicz, L.Li, L.Wang, T.H.Lin, J.Jussif, J.D.Clark, J.B.Telliez, R.P.Robinson, R.Unwalla.

ABSTRACT

Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.