title: Design and evaluation of a series of pyrazolopyrimidines as p70S6K inhibitors.
abstract: The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.
authors.affiliation: Exelixis, 210 E. Grand Avenue, South San Francisco, CA 94080, USA. jbusseni@exelixis.com
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 Canne
authors.initials: LC
authors.lastname: 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: Moon H
authors.initials: MH
authors.lastname: Kim
authors.forename: Rhett R
authors.initials: RR
authors.lastname: Klein
authors.forename: Douglas
authors.initials: D
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
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Rice
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D015195:Drug Design; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D038762:Ribosomal Protein S6 Kinases, 70-kDa