Cancer is a devastating disease that has plagued humans from ancient times to this day. After
decades of slow research progress, promising drug development, and the identification of new targets,
the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling
pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease
in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have
been several promising drug candidates that have been studied, including but not limited to ipatasertib
(RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4;
which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative
activities against human cancer cells. For most of the compounds discussed in this review,
data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated
Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX-
0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development
and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with
ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK-
2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the
suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation.
The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin
derivatives have emerged through pharmacophore modeling, energy-based calculations, and
property predictions.
The Zebrafish Xenograft Models for Investigating Cancer and Cancer Therapeutics
