title: Pyrazolopyrimidines as dual Akt/p70S6K inhibitors.
abstract: Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
authors.affiliation: Exelixis, 210 E. Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Rice
authors.forename: Moon H
authors.initials: MH
authors.lastname: Kim
authors.forename: Joerg
authors.initials: J
authors.lastname: Bussenius
authors.forename: Neel K
authors.initials: NK
authors.lastname: Anand
authors.forename: Charles M
authors.initials: CM
authors.lastname: Blazey
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Bowles
authors.forename: Lynne
authors.initials: L
authors.lastname: Canne-Bannen
authors.forename: Diva S-M
authors.initials: DS
authors.lastname: Chan
authors.forename: Baili
authors.initials: B
authors.lastname: Chen
authors.forename: Erick W
authors.initials: EW
authors.lastname: Co
authors.forename: Simona
authors.initials: S
authors.lastname: Costanzo
authors.forename: Steven C
authors.initials: SC
authors.lastname: DeFina
authors.forename: Larisa
authors.initials: L
authors.lastname: Dubenko
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.forename: Maurizio
authors.initials: M
authors.lastname: Franzini
authors.forename: Ping
authors.initials: P
authors.lastname: Huang
authors.forename: Vasu
authors.initials: V
authors.lastname: Jammalamadaka
authors.forename: Richard G
authors.initials: RG
authors.lastname: Khoury
authors.forename: Rhett R
authors.initials: RR
authors.lastname: Klein
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Laird
authors.forename: Donna T
authors.initials: DT
authors.lastname: Le
authors.forename: Morrison B
authors.initials: MB
authors.lastname: Mac
authors.forename: David J
authors.initials: DJ
authors.lastname: Matthews
authors.forename: David
authors.initials: D
authors.lastname: Markby
authors.forename: Nicole
authors.initials: N
authors.lastname: Miller
authors.forename: John M
authors.initials: JM
authors.lastname: Nuss
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Parks
authors.forename: Tsze H
authors.initials: TH
authors.lastname: Tsang
authors.forename: Amy L
authors.initials: AL
authors.lastname: Tsuhako
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
mesh_terms: D000818:Animals; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa