The p110 isoform is expressed predominantly in leukocytes, and preclinical work showed it to be efficacious in lymphoma and leukemia cells and promoted apoptosis. Accordingly, 106 patients with chronic lymphocytic leukemia, different types of non Hodgkin,s lymphoma, acute myeloid leukemia Dipeptidyl peptidase-4 and multiple myeloma have been enrolled thus far into a phase I study of CAL 101. Reversible increases in liver enzymes and pneumonia have been the most frequent treatment emergent adverse events, although there was minimal hematological toxicity. Impressively, partial responses have been seen in 13 of 23 patients with indolent forms of NHL, 8 of 12 patients with mantle cell lymphoma and 10 of 30 patients with CLL.
Akt inhibitors Direct inhibition of the serine threonine kinase Akt provides GSK1120212 another avenue to pharmacologically regulate activity of the PI3K pathway. The two strategies being explored involves agents that compete for the ATPbinding site and those that act away from this catalytic site. As is the case with PI3K inhibitors, there is some expectation that tumors harboring mutations or amplifications of Akt, or increased pathway activity, will show greater sensitivity to Akt inhibitors. However, as with the rapalogs, the release of feedback inhibition consequent to targeting Akt may enhance the activity of non Akt effectors of PI3K signaling. Further, these non Akt dependent effectors of PI3K signaling, such as SGK3, can promote cancer in the presence of PIK3CA mutations.
Despite these findings, a recent study demonstrated that a noncatalytic site Akt inhibitor was effective against breast cancer cell lines with PIK3CA mutations and HER2 amplifications. In addition, another study demonstrated that tumors with PIK3CA mutations were the most sensitive to an Akt plekstrin homology domain inhibitor, and KRAS mutant tumors were the least sensitive. Perifosine is an allosteric inhibitor that targets the PH domain of Akt, thereby preventing its translocation to the plasma membrane required for activation. It exerts Akt dependent and Akt independent effects, and although many preclinical studies have documented Akt inhibition by perifosine, clinical validation of these findings is lacking. Perifosine has been evaluated in a host of phase I II clinical trials both as monotherapy and in combination with various other agents.
The most common adverse reactions are fatigue and gastrointestinal toxicity. The latter led to frequent treatment discontinuation, alterations to the dosing schedule helped rectify this problem. Single agent activity with perifosine has generally been disappointing, although activity has been observed in patients with sarcoma and Waldenstr?m,s macroglobulinemia. MK 2206 is another allosteric Akt inhibitor. In preclinical studies, synergism has been demonstrated when MK 2206 has been used in combination with other targeted therapies or a host of cytotoxic agents. Preliminary results of a phase I study in solid tumors have been 
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