PDBsum entry 4ytc

Transferase/transferase inhibitor

PDB id: 4ytc

Contents

Protein chain

286 a.a.

Ligands

4HW

Waters ×91

PDB id:

4ytc

Name:

Transferase/transferase inhibitor

Title:

Discovery of vx-509 (decernotinib): a potent and selective janus kinase (jak) 3 inhibitor for the treatment of autoimmune disease

Structure:

Tyrosine-protein kinase jak2. Chain: a. Fragment: unp residues 842-1132. 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:

2.16Å R-factor: 0.191 R-free: 0.213

Authors:

H.J.Zuccola,M.Ledeboer

Key ref:

L.J.Farmer et al. (2015). Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases. J Med Chem, 58, 7195-7216. PubMed id: 26230873 DOI: 10.1021/acs.jmedchem.5b00301

Date:

17-Mar-15 Release date: 12-Aug-15

Protein chain

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

Seq: 1132 a.a.

Struc: 286 a.a.

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.5b00301

J Med Chem 58:7195-7216 (2015)

PubMed id: 26230873

Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.

L.J.Farmer, M.W.Ledeboer, T.Hoock, M.J.Arnost, R.S.Bethiel, Y.L.Bennani, J.J.Black, C.L.Brummel, A.Chakilam, W.A.Dorsch, B.Fan, J.E.Cochran, S.Halas, E.M.Harrington, J.K.Hogan, D.Howe, H.Huang, D.H.Jacobs, L.M.Laitinen, S.Liao, S.Mahajan, V.Marone, G.Martinez-Botella, P.McCarthy, D.Messersmith, M.Namchuk, L.Oh, M.S.Penney, A.C.Pierce, S.A.Raybuck, A.Rugg, F.G.Salituro, K.Saxena, D.Shannon, D.Shlyakter, L.Swenson, S.K.Tian, C.Town, J.Wang, T.Wang, M.W.Wannamaker, R.J.Winquist, H.J.Zuccola.

ABSTRACT

While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.