title: Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.
abstract: A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. adrians@amgen.com
authors.forename: Adrian L
authors.initials: AL
authors.lastname: Smith
authors.forename: Noel D
authors.initials: ND
authors.lastname: D'Angelo
authors.forename: Yunxin Y
authors.initials: YY
authors.lastname: Bo
authors.forename: Shon K
authors.initials: SK
authors.lastname: Booker
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.forename: Brad
authors.initials: B
authors.lastname: Herberich
authors.forename: Fang-Tsao
authors.initials: FT
authors.lastname: Hong
authors.forename: Claire L M
authors.initials: CL
authors.lastname: Jackson
authors.forename: Brian A
authors.initials: BA
authors.lastname: Lanman
authors.forename: Longbin
authors.initials: L
authors.lastname: Liu
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.forename: Liping H
authors.initials: LH
authors.lastname: Pettus
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Reed
authors.forename: Seifu
authors.initials: S
authors.lastname: Tadesse
authors.forename: Nuria A
authors.initials: NA
authors.lastname: Tamayo
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Wurz
authors.forename: Kevin
authors.initials: K
authors.lastname: Yang
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: John D
authors.initials: JD
authors.lastname: McCarter
authors.forename: Tisha San
authors.initials: TS
authors.lastname: Miguel
authors.forename: Leeanne
authors.initials: L
authors.lastname: Zalameda
authors.forename: Jian
authors.initials: J
authors.lastname: Jiang
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.forename: Erin L
authors.initials: EL
authors.lastname: Mullady
authors.forename: Sean
authors.initials: S
authors.lastname: Caenepeel
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Freeman
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Nancy
authors.initials: N
authors.lastname: Zhang
authors.forename: Tian
authors.initials: T
authors.lastname: Wu
authors.forename: Paul E
authors.initials: PE
authors.lastname: Hughes
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000818:Animals; D001682:Biological Availability; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011687:Purines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C575280:4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine; D007191:Indazoles; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013449:Sulfonamides; D013450:Sulfones; D014227:Triazines; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases