PDBsum entry 4ppb

Transferase/transferase inhibitor

PDB id: 4ppb

Contents

Protein chains

239 a.a.

Ligands

2VV ×2

PDB id:

4ppb

Name:

Transferase/transferase inhibitor

Title:

Itk kinase domain with compound 28 (n-{1-[(1s)-3-(dimethylamino)-1- phenylpropyl]-1h-pyrazol-4-yl}-6-(1h-pyrazol-4-yl)-1h-indazole-3- carboxamide)

Structure:

Tyrosine-protein kinase itk/tsk. Chain: a, b. Fragment: kinase domain. Synonym: interleukin-2-inducible t-cell kinase, il-2-inducible t-cell kinase, kinase emt, t-cell-specific kinase, tyrosine-protein kinase lyk. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: itk, emt, lyk. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108

Resolution:

2.82Å R-factor: 0.214 R-free: 0.266

Authors:

C.Eigenbrot,S.Shia

Key ref:

R.M.Pastor et al. (2014). Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors. Bioorg Med Chem Lett, 24, 2448-2452. PubMed id: 24767842 DOI: 10.1016/j.bmcl.2014.04.023

Date:

26-Feb-14 Release date: 04-Jun-14

Protein chains

Q08881  (ITK_HUMAN) -  Tyrosine-protein kinase ITK/TSK from Homo sapiens

Seq: 620 a.a.

Struc: 239 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

DOI no: 10.1016/j.bmcl.2014.04.023

Bioorg Med Chem Lett 24:2448-2452 (2014)

PubMed id: 24767842

Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors.

R.M.Pastor, J.D.Burch, S.Magnuson, D.F.Ortwine, Y.Chen, K.De La Torre, X.Ding, C.Eigenbrot, A.Johnson, M.Liimatta, Y.Liu, S.Shia, X.Wang, L.C.Wu, Z.Pei.

ABSTRACT

There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.