Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.
Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.
Heerding
Dirk A
DA
Oncology Center of Excellence for Drug Discovery, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. dirk.a.heerding@gsk.com
Rhodes
Nelson
N
Leber
Jack D
JD
Clark
Tammy J
TJ
Keenan
Richard M
RM
Lafrance
Louis V
LV
Li
Mei
M
Safonov
Igor G
IG
Takata
Dennis T
DT
Venslavsky
Joseph W
JW
Yamashita
Dennis S
DS
Choudhry
Anthony E
AE
Copeland
Robert A
RA
Lai
Zhihong
Z
Schaber
Michael D
MD
Tummino
Peter J
PJ
Strum
Susan L
SL
Wood
Edgar R
ER
Duckett
Derek R
DR
Eberwein
Derek
D
Knick
Victoria B
VB
Lansing
Timothy J
TJ
McConnell
Randy T
RT
Zhang
Shuyun
S
Minthorn
Elisabeth A
EA
Concha
Nestor O
NO
Warren
Gregory L
GL
Kumar
Rakesh
R
D000818:Animals; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D010069:Oxadiazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity
C528328:GSK690693; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt