title: Substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as multi-targeted inhibitors of insulin-like growth factor-1 receptor (IGF1R) and members of ErbB-family receptor kinases.
abstract: This Letter describes the lead discovery, optimization, and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR, and ErbB2. The leading compound 11 showed an IGF1R IC(50) of 12 nM, an EGFR (L858R) IC(50) of 31 nM, and an ErbB2 IC(50) of 11 nM, potent activity in cellular functional and anti-proliferation assays, as well as activity in an in vivo pharmacodynamic assay.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gary.t.wang@abbott.com
authors.forename: Gary T
authors.initials: GT
authors.lastname: Wang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mantei
authors.forename: Robert D
authors.initials: RD
authors.lastname: Hubbard
authors.forename: Julie L
authors.initials: JL
authors.lastname: Wilsbacher
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lora
authors.initials: L
authors.lastname: Tucker
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Hu
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Osterling
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Jieyi
authors.initials: J
authors.lastname: Wang
authors.forename: Steven K
authors.initials: SK
authors.lastname: Davidsen
authors.forename: Randy L
authors.initials: RL
authors.lastname: Bell
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000225:Adenine; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; C414764:8-aza-7-deazaadenine