The Akt/PKB Family of Protein Kinases: A Review of Small Molecule Inhibitors and Progress Towards Target Validation

Abstract

This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for chemotherapy and it has been postulated that inhibition of Akt alone or in combination with standard cancer chemotherapeutics will reduce the apoptotic threshold and preferentially kill cancer cells. The development of specific and potent inhibitors will allow this hypothesis to be tested in animals. The majority of small molecule inhibitors in this nascent field are classic ATP-competitive inhibitors which provide little specificity. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other PH domain containing proteins and may have poor bioavailability. None of the inhibitors in these classes have been reported to have Akt isozyme specificity. Recently, novel allosteric inhibitors have been reported which are pleckstrin homology domain dependent and exhibit Akt isozyme selectivity. Inhibitors in this class may have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.

Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

“…The combination of statins and LY294002 might bring the level of Akt activity below a threshold level that maintains cell survival (34). Alternatively, different isoforms of Akt may have overlapping roles (35,36) and LY294002 and statins might inhibit different isoforms of Akt.…”

Inhibition of Akt pathways in the treatment of prostate cancer

“…Preclinical data on many Akt inhibitors are available and are reviewed in detail elsewhere. [28][29][30][31] Additional data regarding the Akt inhibitory properties of several nutriceuticals is emerging and may prove important in the future. Examples include quercetin, 32 diallyl trisulfide, 33 curcumin 34 and silymarin.…”

Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition

“…The Protein kinase B (Akt/PKB) serine/threonine protein kinases play major roles in signal transduction, cell growth, proliferation and inhibition of apoptosis (see reviews Datta et al, 1999;Thompson and Thompson, 2004;Altomare and Testa, 2005;Barnett et al, 2005;Cheng et al, 2005;Testa and Tsichlis, 2005;Granville et al, 2006). There are three structurally related homologues in humans designated as Akt1, Akt2 and Akt3.…”