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.
Beta-glucuronidase (bG) is a potential biomarker for cancer diagnosis and prodrug therapy. The ability to image bG activity in patients would assist in personalized glucuronide prodrug cancer therapy. However, whole-body imaging of bG activity for medical usage is not yet available. Here, we developed a radioactive bG activity-based trapping probe for positron emission tomography (PET). We generated a 124 I-tyramine-conjugated difluoromethylphenol beta-glucuronide probe (TrapG) to form 124 I-TrapG that could be selectively activated by bG for subsequent attachment of 124 I-tyramine to nucleophilic moieties near bG-expressing sites. We estimated the specificity of a fluorescent FITC-TrapG, the cytotoxicity of tyramine-TrapG, and the serum half-life of 124 I-TrapG. bG targeting of 124 I-TrapG in vivo was examined by micro-PET. The biodistribution of 131 I-TrapG was investigated in different organs. Finally, we imaged the endogenous bG activity and assessed its correlation with therapeutic efficacy of 9-aminocamptothecin glucuronide (9ACG) prodrug in native tumors. FITC-TrapG showed specific trapping at bG-expressing CT26 (CT26/mbG) cells but not in CT26 cells. The native TrapG probe possessed low cytotoxicity. 124 ITrapG preferentially accumulated in CT26/mbG but not CT26 cells. Meanwhile, micro-PET and wholebody autoradiography results demonstrated that 124 I-TrapG signals in CT26/mbG tumors were 141.4-fold greater than in CT26 tumors. Importantly, Colo205 xenografts in nude mice that express elevated endogenous bG can be monitored by using infrared glucuronide trapping probes (NIR-TrapG) and suppressed by 9ACG prodrug treatment. 124 I-TrapG exhibited low cytotoxicity allowing long-term monitoring of bG activity in vivo to aid in the optimization of prodrug targeted therapy.
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