title: Discovery and optimization of a series of 3-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amines: orally bioavailable, selective, and potent ATP-independent Akt inhibitors.
abstract: This paper describes the implementation of a biochemical and biophysical screening strategy to identify and optimize small molecule Akt1 inhibitors that act through a mechanism distinct from that observed for kinase domain ATP-competitive inhibitors. With the aid of an unphosphorylated Akt1 cocrystal structure of 12j solved at 2.25 Å, it was possible to confirm that as a consequence of binding these novel inhibitors, the ATP binding cleft contained a number of hydrophobic residues that occlude ATP binding as expected. These Akt inhibitors potently inhibit intracellular Akt activation and its downstream target (PRAS40) in vitro. In vivo pharmacodynamic and pharmacokinetic studies with two examples, 12e and 12j, showed the series to be similarly effective at inhibiting the activation of Akt and an additional downstream effector (p70S6) following oral dosing in mice.
authors.affiliation: ArQule Inc., 19 Presidential Way, Woburn, Massachusetts 01801, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashwell
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lapierre
authors.forename: Christopher
authors.initials: C
authors.lastname: Brassard
authors.forename: Karen
authors.initials: K
authors.lastname: Bresciano
authors.forename: Cathy
authors.initials: C
authors.lastname: Bull
authors.forename: Susan
authors.initials: S
authors.lastname: Cornell-Kennon
authors.forename: Sudharshan
authors.initials: S
authors.lastname: Eathiraj
authors.forename: Dennis S
authors.initials: DS
authors.lastname: France
authors.forename: Terence
authors.initials: T
authors.lastname: Hall
authors.forename: Jason
authors.initials: J
authors.lastname: Hill
authors.forename: Eoin
authors.initials: E
authors.lastname: Kelleher
authors.forename: Sampada
authors.initials: S
authors.lastname: Khanapurkar
authors.forename: Darin
authors.initials: D
authors.lastname: Kizer
authors.forename: Steffi
authors.initials: S
authors.lastname: Koerner
authors.forename: Jeff
authors.initials: J
authors.lastname: Link
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Liu
authors.forename: Sapna
authors.initials: S
authors.lastname: Makhija
authors.forename: Magdi
authors.initials: M
authors.lastname: Moussa
authors.forename: Nivedita
authors.initials: N
authors.lastname: Namdev
authors.forename: Khanh
authors.initials: K
authors.lastname: Nguyen
authors.forename: Robert
authors.initials: R
authors.lastname: Nicewonger
authors.forename: Rocio
authors.initials: R
authors.lastname: Palma
authors.forename: Jeff
authors.initials: J
authors.lastname: Szwaya
authors.forename: Manish
authors.initials: M
authors.lastname: Tandon
authors.forename: Uma
authors.initials: U
authors.lastname: Uppalapati
authors.forename: David
authors.initials: D
authors.lastname: Vensel
authors.forename: Laurie P
authors.initials: LP
authors.lastname: Volak
authors.forename: Erika
authors.initials: E
authors.lastname: Volckova
authors.forename: Neil
authors.initials: N
authors.lastname: Westlund
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.forename: Rui-Yang
authors.initials: RY
authors.lastname: Yang
authors.forename: Thomas C K
authors.initials: TC
authors.lastname: Chan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors; D000255:Adenosine Triphosphate / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C484523:AKT1S1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D007093:Imidazoles; D011725:Pyridines; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa