PDBsum entry 3h3c

Transferase

PDB id: 3h3c

Contents

Protein chain

263 a.a. *

Ligands

SO4 ×5

P1E

Waters ×29

* Residue conservation analysis

PDB id:

3h3c

Name:

Transferase

Title:

Crystal structure of pyk2 in complex with sulfoximine-substituted trifluoromethylpyrimidine analog

Structure:

Protein tyrosine kinase 2 beta. Chain: a. Synonym: focal adhesion kinase 2, fadk 2, proline-rich tyrosine kinase 2, cell adhesion kinase beta, cak beta, calcium-dependent tyrosine kinase, cadtk, related adhesion focal tyrosine kinase, raftk. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ptk2b, fak2, pyk2, raftk. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469

Resolution:

2.00Å R-factor: 0.225 R-free: 0.273

Authors:

S.Han,A.Mistry

Key ref:

D.P.Walker et al. (2009). Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity. Bioorg Med Chem Lett, 19, 3253-3258. PubMed id: 19428251

Date:

16-Apr-09 Release date: 26-May-09

Protein chain

Q14289  (FAK2_HUMAN) -  Protein-tyrosine kinase 2-beta from Homo sapiens

Seq: 1009 a.a.

Struc: 263 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

Bioorg Med Chem Lett 19:3253-3258 (2009)

PubMed id: 19428251

Sulfoximine-substituted trifluoromethylpyrimidine analogs as inhibitors of proline-rich tyrosine kinase 2 (PYK2) show reduced hERG activity.

D.P.Walker, M.P.Zawistoski, M.A.McGlynn, J.C.Li, D.W.Kung, P.C.Bonnette, A.Baumann, L.Buckbinder, J.A.Houser, J.Boer, A.Mistry, S.Han, L.Xing, A.Guzman-Perez.

ABSTRACT

The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.