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.
MeSH terms
-
Adaptor Proteins, Signal Transducing / antagonists & inhibitors
-
Adenosine Triphosphate / physiology*
-
Administration, Oral
-
Animals
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Biological Availability
-
Catalytic Domain
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Crystallography, X-Ray
-
Humans
-
Imidazoles / chemical synthesis*
-
Imidazoles / chemistry
-
Imidazoles / pharmacology
-
Mice
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Phosphorylation
-
Protein Binding
-
Protein Conformation
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
-
Pyridines / chemical synthesis*
-
Pyridines / chemistry
-
Pyridines / pharmacology
-
Ribosomal Protein S6 Kinases, 70-kDa / antagonists & inhibitors
-
Structure-Activity Relationship
Substances
-
AKT1S1 protein, human
-
Adaptor Proteins, Signal Transducing
-
Antineoplastic Agents
-
Imidazoles
-
Pyridines
-
Adenosine Triphosphate
-
Proto-Oncogene Proteins c-akt
-
Ribosomal Protein S6 Kinases, 70-kDa