Discovery of 5-pyrrolopyridinyl-2-thiophenecarboxamides as potent AKT kinase inhibitors.
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.
Seefeld
Mark A
MA
Oncology Chemistry, GlaxoSmithKline, Collegeville, PA 19426, USA.
Rouse
Meagan B
MB
McNulty
Kenneth C
KC
Sun
Lihui
L
Wang
Jizhou
J
Yamashita
Dennis S
DS
Luengo
Juan I
JI
Zhang
Shuyun
S
Minthorn
Elisabeth A
EA
Concha
Nestor O
NO
Heerding
Dirk A
DA
D000818:Animals; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D058924:Thienopyridines; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C543087:5-pyrrolopyridinyl-2-thiophenecarboxamide; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D058924:Thienopyridines; D013876:Thiophenes; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt