PDBsum entry 5hhw

Transferase

PDB id: 5hhw

Contents

Protein chain

306 a.a.

Ligands

60O

EDO

Waters ×320

PDB id:

5hhw

Name:

Transferase

Title:

Crystal structure of insulin receptor kinase domain in complex with cis-(r)-7-(3-(azetidin-1-ylmethyl)cyclobutyl)-5-(3-((tetrahydro-2h- pyran-2-yl)methoxy)phenyl)-7h-pyrrolo[2,3-d]pyrimidin-4-amine.

Structure:

Insulin receptor. Chain: a. Fragment: kinase domain, residues 1005-1310. Synonym: ir. Engineered: yes. Mutation: yes

Source:

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

Resolution:

1.79Å R-factor: 0.172 R-free: 0.198

Authors:

C.Scheufler,A.Izaac,F.Stauffer

Key ref:

F.Stauffer et al. (2016). Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors. Bioorg Med Chem Lett, 26, 2065-2067. PubMed id: 26951750 DOI: 10.1016/j.bmcl.2016.02.074

Date:

11-Jan-16 Release date: 13-Apr-16

Protein chain

P06213  (INSR_HUMAN) -  Insulin receptor from Homo sapiens

Seq: 1382 a.a.

Struc: 306 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.7.10.1 - receptor 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.2016.02.074

Bioorg Med Chem Lett 26:2065-2067 (2016)

PubMed id: 26951750

Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors.

F.Stauffer, S.W.Cowan-Jacob, C.Scheufler, P.Furet.

ABSTRACT

We report structure-guided modifications of the benzyloxy substituent of the Insulin-like Growth Factor-1 Receptor (IGF-1R) inhibitor NVP-AEW541. This chemical group has been shown to confer selectivity against other protein kinases but at the expense of a metabolism liability. X-ray crystallography has revealed that the benzyloxy moiety interacts with a lysine cation of the IGF-1R kinase domain via its ether function and its aromatic π-system and is nicely embedded in an induced hydrophobic pocket. We show that 1,4-diethers displaying an adequate hydrophobic and constrained shape are advantageous benzyloxy replacements. A single digit nanomolar inhibitor (compound 20, IC50=8.9nM) was identified following this approach.