title: Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold.
abstract: Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193 nM (91 ng/mL).
authors: Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. rwurz@amgen.com
authors: Ryan P
authors: RP
authors: Wurz
authors: Longbin
authors: L
authors: Liu
authors: Kevin
authors: K
authors: Yang
authors: Nobuko
authors: N
authors: Nishimura
authors: Yunxin
authors: Y
authors: Bo
authors: Liping H
authors: LH
authors: Pettus
authors: Sean
authors: S
authors: Caenepeel
authors: Daniel J
authors: DJ
authors: Freeman
authors: John D
authors: JD
authors: McCarter
authors: Erin L
authors: EL
authors: Mullady
authors: Tisha San
authors: TS
authors: Miguel
authors: Ling
authors: L
authors: Wang
authors: Nancy
authors: N
authors: Zhang
authors: Kristin L
authors: KL
authors: Andrews
authors: Douglas A
authors: DA
authors: Whittington
authors: Jian
authors: J
authors: Jiang
authors: Raju
authors: R
authors: Subramanian
authors: Paul E
authors: PE
authors: Hughes
authors: Mark H
authors: MH
authors: Norman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D014227:Triazines