title: Discovery of novel insulin-like growth factor-1 receptor inhibitors with unique time-dependent binding kinetics.
abstract: This letter describes a series of small molecule inhibitors of IGF-1R with unique time-dependent binding kinetics and slow off-rates. Structure-activity and structure-kinetic relationships were elucidated and guided further optimizations within the series, culminating in compound 2. With an IGF-1R dissociative half-life (t 1/2) of >100 h, compound 2 demonstrated significant and extended PD effects in conjunction with tumor growth inhibition in xenograft models at a remarkably low and intermittent dose, which correlated with the observed in vitro slow off-rate properties.
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Meizhong
authors.initials: M
authors.lastname: Jin
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Brenda A
authors.initials: BA
authors.lastname: Petronella
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Andy
authors.initials: A
authors.lastname: Cooke
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Mridula
authors.initials: M
authors.lastname: Kadalbajoo
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Kam W
authors.initials: KW
authors.lastname: Siu
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kleinberg
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Earl W
authors.initials: EW
authors.lastname: May
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Prafulla C
authors.initials: PC
authors.lastname: Gokhale
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Schulz
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kahler
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bittner
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Foreman
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Pachter
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: David
authors.initials: D
authors.lastname: Epstein
authors.affiliation: OSI Pharmaceuticals, LLC , A wholly owned subsidiary of Astellas US LLC, 1 Bioscience Park Drive, Farmingdale, New York 11735, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mulvihill
keywords: Insulin-like growth factor-1 receptor (IGF-1R); cancer; slow off-rate; time-dependent inhibition