PI3K and Structurally Related Kinases

1 PI3K-a Inhibitors, pan-PI3K Inhibitors and Dual mTOR-PI3K-a Inhibitors 

The morpholine and sulfonyl groups are engaged in similar interactions as observed for GDC-0941. The aminopyridine interacts with Asp-836 and Asp-841. 

MEK inhibitor selumetinib (AZD6244, AstraZeneca).94,95 In 2010, BKM120 advanced to a Phase I II trial as a combination therapy with trastuzumab in breast cancer patients. A second compound, BYL719, began a Phase II trial in late 2010 in patients with solid tumors with a mutation of the PIK3CA gene however, the properties and biological activities of this compound have yet to be disclosed. 

Bayer initiated clinical trials in patients with advanced solid tumors with BAY 80-6946 (54) in 2009. This compound displayed an IC50 of 0.5 nM against PI3K-a and inhibited mTOR with an IC50 of 45 nM, while being 

As mentioned, due to the homology between mTOR and PI3K, many inhibitors will affect both enzymes. However, since mTOR is located downstream of PI3K it has been postulated that selective inhibition of mTOR may also lead to effective cancer therapeutics while minimizing the side effects associated with pan-PI3K inhibition. Selective mTOR inhibitors may be divided into two classes. The first class consists of the allosteric inhibitors derived from rapamycin, which selectively inhibit mTORCl by binding to FKBP12 and 

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