Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo.
The Akt kinases are central nodes in signal transduction pathways that are important for cellular transformation and tumor progression. We report the development of a series of potent and selective indazole-pyridine based Akt inhibitors. These compounds, exemplified by A-443654 (K(i) = 160 pmol/L versus Akt1), inhibit Akt-dependent signal transduction in cells and in vivo in a dose-responsive manner. In vivo, the Akt inhibitors slow the progression of tumors when used as monotherapy or in combination with paclitaxel or rapamycin. Tumor growth inhibition was observed during the dosing interval, and the tumors regrew when compound administration was ceased. The therapeutic window for these compounds is narrow. Efficacy is achieved at doses approximately 2-fold lower than the maximally tolerated doses. Consistent with data from knockout animals, the Akt inhibitors induce an increase in insulin secretion. They also induce a reactive increase in Akt phosphorylation. Other toxicities observed, including malaise and weight loss, are consistent with abnormalities in glucose metabolism. These data show that direct Akt inhibition may be useful in cancer therapy, but significant metabolic toxicities are likely dose limiting.
Luo
Yan
Y
Cancer Research, Abbott Laboratories, IL 60064-6117, USA.
Shoemaker
Alexander R
AR
Liu
Xuesong
X
Woods
Keith W
KW
Thomas
Sheela A
SA
de Jong
Ron
R
Han
Edward K
EK
Li
Tongmei
T
Stoll
Vincent S
VS
Powlas
Jessica A
JA
Oleksijew
Anatol
A
Mitten
Michael J
MJ
Shi
Yan
Y
Guan
Ran
R
McGonigal
Thomas P
TP
Klinghofer
Vered
V
Johnson
Eric F
EF
Leverson
Joel D
JD
Bouska
Jennifer J
JJ
Mamo
Mulugeta
M
Smith
Richard A
RA
Gramling-Evans
Emily E
EE
Zinker
Bradley A
BA
Mika
Amanda K
AK
Nguyen
Phong T
PT
Oltersdorf
Tilman
T
Rosenberg
Saul H
SH
Li
Qun
Q
Giranda
Vincent L
VL
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013379:Substrate Specificity
C504035:A 443654; D000970:Antineoplastic Agents; D007191:Indazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C023666:pyridine