PDBsum entry 4bbf

Transferase

PDB id: 4bbf

Contents

Protein chain

288 a.a.

Ligands

O19 ×4

Waters ×435

PDB id:

4bbf

Name:

Transferase

Title:

Aminoalkylpyrimidine inhibitor complexes with jak2

Structure:

Tyrosine-protein kinase jak2. Chain: a, b, c, d. Fragment: protein tyrosine kinase domain, residues 839-1132. Synonym: janus kinase 2, jak-2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.

Resolution:

2.00Å R-factor: 0.232 R-free: 0.289

Authors:

J.Li

Key ref:

T.Forsyth et al. (2012). SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors. Bioorg Med Chem Lett, 22, 7653-7658. PubMed id: 23127890

Date:

21-Sep-12 Release date: 21-Nov-12

Protein chains

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

Seq: 1132 a.a.

Struc: 288 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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

Bioorg Med Chem Lett 22:7653-7658 (2012)

PubMed id: 23127890

SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.

T.Forsyth, P.C.Kearney, B.G.Kim, H.W.Johnson, N.Aay, A.Arcalas, D.S.Brown, V.Chan, J.Chen, H.Du, S.Epshteyn, A.A.Galan, T.P.Huynh, M.A.Ibrahim, B.Kane, E.S.Koltun, G.Mann, L.E.Meyr, M.S.Lee, G.L.Lewis, R.T.Noguchi, M.Pack, B.H.Ridgway, X.Shi, C.S.Takeuchi, P.Zu, J.W.Leahy, J.M.Nuss, R.Aoyama, S.Engst, S.B.Gendreau, R.Kassees, J.Li, S.H.Lin, J.F.Martini, T.Stout, P.Tong, J.Woolfrey, W.Zhang, P.Yu.

ABSTRACT

We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.