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Tumor cells upregulate many cell signaling pathways, with AKT being one of the key kinases to be activated in a variety of malignancies. GSK2110183 and GSK2141795 are orally bioavailable, potent inhibitors of the AKT kinases that have progressed to human clinical studies. Both compounds are selective, ATP-competitive inhibitors of AKT 1, 2 and 3. Cells treated with either compound show decreased phosphorylation of several substrates downstream of AKT. Both compounds have desirable pharmaceutical properties and daily oral dosing results in a sustained inhibition of AKT activity as well as inhibition of tumor growth in several mouse tumor models of various histologic origins. Improved kinase selectivity was associated with reduced effects on glucose homeostasis as compared to previously reported ATP-competitive AKT kinase inhibitors. In a diverse cell line proliferation screen, AKT inhibitors showed increased potency in cell lines with an activated AKT pathway (via PI3K/PTEN mutation or loss) while cell lines with activating mutations in the MAPK pathway (KRAS/BRAF) were less sensitive to AKT inhibition. Further investigation in mouse models of KRAS driven pancreatic cancer confirmed that combining the AKT inhibitor, GSK2141795 with a MEK inhibitor (GSK2110212; trametinib) resulted in an enhanced anti-tumor effect accompanied with greater reduction in phospho-S6 levels. Taken together these results support clinical evaluation of the AKT inhibitors in cancer, especially in combination with MEK inhibitor.

β-Amyloid peptides (Aβ40 and Aβ42) are the major constituents of amyloid plaques, which are one of the hallmarks of Alzheimer's disease (AD). The Aβ is derived from sequential cleavages of amyloid precursor protein (APP) by β- and γ-secretases. γ-Secretase consists of at least four proteins where presenilins (PS1 and PS2 or PS) are the catalytic subunit involved in the γ-site cleavage of APP. Secretion of both Aβ40 and Aβ42 is significantly reduced in PS1 knock-out cells and completely abolished in cells deficient for both PS1 and PS2. Consequently, both the PS proteins play essential roles in the production of the secretory of Aβ from cells. Recent studies in primary neurons, however, suggest that PSs are not required for intracellular Aβ42 accumulation; thus the intracellular Aβ42 appears to be generated in a PS-independent manner. Here we present the first biochemical evidence indicating that Aβ, especially Aβ42, can be generated in the absence of PS based on an in vitroγ-secretase assay employing membranes prepared from PS-deficient Blastocyst-derived (BD) cells. This PS-independent γ-secretase (PSIG) activity is sensitive to the changes in pH and displays an optimal activity at pH 6.0. Pepstatin A is a potent inhibitor for this proteolytic activity with IC50 of 1.2 n m and 0.4 n m for Aβ40 and Aβ42 generation, respectively. These results indicate that these PS-independent γ-site cleavages are mediated by an aspartyl protease. More importantly, the PSIG activity displays a distinct preference in mediating the 42-site cleavage over the 40-site cleavage, thereby generating Aβ42 as the predominant product. [ABSTRACT FROM AUTHOR]