title: Identification of a 5-[3-phenyl-(2-cyclic-ether)-methylether]-4-aminopyrrolo[2,3-d]pyrimidine series of IGF-1R inhibitors.
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.
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Postfach, 4002 Basel, Switzerland. Electronic address: frederic.stauffer@novartis.com.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Stauffer
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Postfach, 4002 Basel, Switzerland.
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Postfach, 4002 Basel, Switzerland.
authors.forename: Clemens
authors.initials: C
authors.lastname: Scheufler
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Postfach, 4002 Basel, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C000612664:5-(3-phenyl-(2-cyclic-ether)-methylether)-4-aminopyrrolo(2,3-d)pyrimidine; C501177:NVP-AEW541; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1
keywords: IGF-1R X-ray co-crystal structure; IGF-1R inhibitor; Structure-guided design