Abstract
A pyrrolopyridinyl thiophene carboxamide 7 was discovered as a tractable starting point for a lead optimization effort in an AKT kinase inhibition program. SAR studies aided by a co-crystal structure of 7 in AKT2 led to the identification of AKT inhibitors with subnanomolar potency. Representative compounds showed antiproliferative activity as well as inhibition of phosphorylation of the downstream target GSK3beta.
MeSH terms
-
Animals
-
Crystallography, X-Ray
-
Drug Discovery* / methods
-
Humans
-
Mice
-
Protein Kinase Inhibitors / chemical synthesis*
-
Protein Kinase Inhibitors / pharmacology
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-akt / metabolism
-
Pyridines / chemical synthesis*
-
Pyridines / pharmacology*
-
Thienopyridines
-
Thiophenes / chemical synthesis
-
Thiophenes / chemistry*
-
Thiophenes / pharmacology
Substances
-
5-pyrrolopyridinyl-2-thiophenecarboxamide
-
Protein Kinase Inhibitors
-
Pyridines
-
Thienopyridines
-
Thiophenes
-
AKT2 protein, human
-
Proto-Oncogene Proteins c-akt