title: Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors.
abstract: mTOR is a critical regulator of cellular signaling downstream of multiple growth factors. The mTOR/PI3K/AKT pathway is frequently mutated in human cancers and is thus an important oncology target. Herein we report the evolution of our program to discover ATP-competitive mTOR inhibitors that demonstrate improved pharmacokinetic properties and selectivity compared to our previous leads. Through targeted SAR and structure-guided design, new imidazopyridine and imidazopyridazine scaffolds were identified that demonstrated superior inhibition of mTOR in cellular assays, selectivity over the closely related PIKK family and improved in vivo clearance over our previously reported benzimidazole series.
authors: Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. epeterso@amgen.com
authors: Emily A
authors: EA
authors: Peterson
authors: Alessandro A
authors: AA
authors: Boezio
authors: Paul S
authors: PS
authors: Andrews
authors: Christiane M
authors: CM
authors: Boezio
authors: Tammy L
authors: TL
authors: Bush
authors: Alan C
authors: AC
authors: Cheng
authors: Deborah
authors: D
authors: Choquette
authors: James R
authors: JR
authors: Coats
authors: Adria E
authors: AE
authors: Colletti
authors: Katrina W
authors: KW
authors: Copeland
authors: Michelle
authors: M
authors: DuPont
authors: Russell
authors: R
authors: Graceffa
authors: Barbara
authors: B
authors: Grubinska
authors: Joseph L
authors: JL
authors: Kim
authors: Richard T
authors: RT
authors: Lewis
authors: Jingzhou
authors: J
authors: Liu
authors: Erin L
authors: EL
authors: Mullady
authors: Michele H
authors: MH
authors: Potashman
authors: Karina
authors: K
authors: Romero
authors: Paul L
authors: PL
authors: Shaffer
authors: Mary K
authors: MK
authors: Stanton
authors: John C
authors: JC
authors: Stellwagen
authors: Yohannes
authors: Y
authors: Teffera
authors: Shuyan
authors: S
authors: Yi
authors: Ti
authors: T
authors: Cai
authors: Daniel S
authors: DS
authors: La
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011725:Pyridines; D058570:TOR Serine-Threonine Kinases; C062482:pyridazine; C029899:imidazole; C031000:benzimidazole; C023666:pyridine