title: Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor.
abstract: BACKGROUND
  The IGF-1 receptor (IGF-1R) has been implicated in the promotion of tumorigenesis, metastasis and resistance to cancer therapies. Therefore, this receptor has become a major focus for the development of anticancer agents.
  
  
  RESULTS
  Our lead optimization efforts that blended structure-based design and empirical medicinal chemistry led to the discovery of OSI-906, a novel small-molecule dual IGF-1R/insulin receptor (IR) kinase inhibitor. OSI-906 potently and selectively inhibits autophosphorylation of both human IGF-1R and IR, displays in vitro antiproliferative effects in a variety of tumor cell lines and shows robust in vivo anti-tumor efficacy in an IGF-1R-driven xenograft model when administered orally once daily.
  
  
  CONCLUSIONS
  OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable preclinical drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing.
authors.affiliation: (OSI) Oncology, OSI Pharmaceuticals, Inc., 41 Pinelawn, Melville, NY 11747, USA. mmulvihill@osip.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulvihill
authors.forename: Andrew
authors.initials: A
authors.lastname: Cooke
authors.forename: Maryland
authors.initials: M
authors.lastname: Rosenfeld-Franklin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Buck
authors.forename: Ken
authors.initials: K
authors.lastname: Foreman
authors.forename: Darla
authors.initials: D
authors.lastname: Landfair
authors.forename: Matthew
authors.initials: M
authors.lastname: O'Connor
authors.forename: Caroline
authors.initials: C
authors.lastname: Pirritt
authors.forename: Yingchaun
authors.initials: Y
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Yao
authors.forename: Lee D
authors.initials: LD
authors.lastname: Arnold
authors.forename: Neil W
authors.initials: NW
authors.lastname: Gibson
authors.forename: Qun-Sheng
authors.initials: QS
authors.lastname: Ji
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002460:Cell Line; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D011487:Protein Conformation; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000970:Antineoplastic Agents; D007093:Imidazoles; D011719:Pyrazines; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin