Discovery of Akt Kinase Inhibitors through Structure-Based Virtual Screening and Their Evaluation as Potential Anticancer Agents

Abstract

Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC50 values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC50 for HEK-293/IC50 for HCT-116) of 12.5 and 16.1, respectively. Through structure-based virtual screening and biological evaluations, we have successfully identified several new Akt inhibitors that displayed cytotoxic activity against HCT-116 human colon cancer cells. Especially, Compounds a46 and a48 may serve as useful lead compounds for further development of new anticancer agents.

The relationship between TRAF6 and tumors

“…3). AKT is activated by phosphorylation of Thr308 and Ser473 and subsequently phosphorylates a variety of downstream protein substrates [29]. Phosphorylated AKT (pAKT) engages in the dysregulation of apoptosis, proliferation, and cell movement [30].…”

AKT as a Therapeutic Target for Cancer

“…1). AKT is activated by phosphorylation on Thr308 or Ser473 and it phosphorylates a variety of downstream protein substrates, including GSK3b, Bcl-2-associated death promoter, forkhead in rhabdomyosarcoma, and mouse double minute 2 homolog (2). Phosphorylated AKT (pAKT) has been implicated in the deregulation of apoptosis, proliferation, and cell motility because of its induction of signals that interfere with normal regulatory mechanisms activating mTOR (3,4).…”

Discovery of new AKT1 inhibitors by combination of in silico structure based virtual screening approaches and biological evaluations

“…Cell line tests on two of these ligands indicated apoptosis. Alternatively, Chuang et al 9 employed solely structure-based docking. From 48 promising candidates, 12 compounds displayed comparable or more potent cytotoxic activity compared to the reference compound, H-89, against HCT-116 colon cancer cells.…”