title: Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity.
abstract: A series of novel 7-amino-1,3,4,5-tetrahydrobenzo[b]azepin-2-one derivatives within the diaminopyrimidine class of kinase inhibitors were identified that target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an isolated enzyme assay and inhibit autophosphorylation of the oncogenic fusion protein NPM-ALK in anaplastic large cell lymphoma (ALCL) cell lines. The lead inhibitor 15, which incorporates a bicyclo[2.2.1]hept-5-ene ring system in place of an aryl moiety, activates the pro-apoptotic caspases (3 and 7) and displays selective cytotoxicity against ALK-positive ALCL cells. Furthermore, 15 provides more than 40-fold selectivity against the structurally related insulin receptor, is orally bioavailable in multiple species, and displays in vivo antitumor efficacy when dosed orally in ALK-positive ALCL tumor xenografts in Scid mice.
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Ott
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Rabindranath
authors.initials: R
authors.lastname: Tripathy
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Mangeng
authors.initials: M
authors.lastname: Cheng
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Robert
authors.initials: R
authors.lastname: McHugh
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Anzalone
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Ted L
authors.initials: TL
authors.lastname: Underiner
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Curry
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Quail
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Lihui
authors.initials: L
authors.lastname: Lu
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Weihua
authors.initials: W
authors.lastname: Wan
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.affiliation: Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
keywords: ALCL; ALK; Anaplastic lymphoma kinase inhibitor; anaplastic large cell lymphoma