PDBsum entry 5hhw

Transferase

PDB id: 5hhw

Contents

Protein chain

306 a.a.

Ligands

60O

EDO

Waters ×320

References listed in PDB file

Key reference

• Title: Identification of a 5-[3-Phenyl-(2-Cyclic-Ether)-Methylether]-4-Aminopyrrolo[2,3-D]pyrimidine series of igf-1r inhibitors.
• Authors: F.Stauffer, S.W.Cowan-Jacob, C.Scheufler, P.Furet.
• Ref.: Bioorg Med Chem Lett, 2016, 26, 2065-2067. [DOI no: 10.1016/j.bmcl.2016.02.074]
• PubMed id: 26951750

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.