5HHW

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.

Summary for 5HHW

• Entry DOI: 10.2210/pdb5hhw/pdb
• Descriptor: Insulin receptor, 7-[3-(azetidin-1-ylmethyl)cyclobutyl]-5-[3-[[(2~{R})-oxan-2-yl]methoxy]phenyl]pyrrolo[2,3-d]pyrimidin-4-amine, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, insulin receptor, kinase, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: P06213
• Total number of polymer chains: 1
• Total formula weight: 35448.66

Authors

Scheufler, C.,Izaac, A.,Stauffer, F. (deposition date: 2016-01-11, release date: 2016-04-13, Last modification date: 2024-05-01)

Primary citation

Stauffer, F.,Cowan-Jacob, S.W.,Scheufler, C.,Furet, P.
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, 2016

PubMed 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=8.9 nM) was identified following this approach.

PubMed: 26951750
DOI: 10.1016/j.bmcl.2016.02.074

Experimental method

X-RAY DIFFRACTION (1.79 Å)