PI3K In Medicine
As mentioned previously, the class I PI3Ks play a critical role in the transmission of proliferation and survival signals in a wide variety of cell types. Due to PI3Ks intricate activation system by numerous targets, mutations at key positions in PI3K have been identified to cause various types of cancer. These positions are known as “Hotspots.” These hotspots are located in both the p85 subunit and p110 subunit. For example, a mutation in the known to cause glioblastoma is G376R. a crucial residue in one of the stabilizing C2 domain loops. [6] Somatic mutations in the gene encoding the p110 catalytic subunit can be grouped into the four classes of the catalytic subunit in which they occur, the ABD, C2, helical and catalytic domains, all of which likely increase PI3K activity by different mechanisms.[10] For example, two well known cancer causing mutations map to , at residues . These residues lie at the interface of the ABD and Kinase domains and are believed to alter regulation of the catalytic subunit. Other mutations, such as those in the C2 domain, up regulate PI3K, by increasing the affinity for substrate containing membranes, resulting in elevated levels of PIP3. [10] Aberrations in PIP3 levels, either through activation of PI3Ks or through inactivation of lipid phosphatase PTEN, occur frequently in numerous forms of cancer. Recent data suggest that at least 50% of human breast cancers involve mutations in either PI3K or PTEN. [10]
The dramatic number of mutations in PI3K associated with Cancer has resulted in PIK3CA, the gene that encodes the catalytic p100( domain of PIK3, being identified as a human oncogene. More than 1500 PIK3CA mutations, nearly all of which increase lipid kinase activity, have been identified in different tumor types, the most common being breast and uterine cancers. [6] Further, the lipid products of PI3K interact with other well known oncogenes like akt2, akt3, PDGFR, PTEN, among many others. [7]
In addition to cancer, faulty PI3K function has been associated with disorders like heart failure [11], diabetes, [12], and inflammation.[13]
Current Pharmaceutical Approaches
Broad spectrum PI3K inhibitors have exhibited impressive results, revealing increased apoptosis and decreased proliferation in tumor models.[10] The primary focus now amongst medicinal researchers is to identify PI3K inhibitors with increased selectivity (particularly for p110) and bioavailability. Use of inhibitors such as wortmannin have identified slightly different binding mechanisms between PI3K isoforms, creating the potential for highly selective compounds to neutralize secific PI3K isotypes while leaving other forms of the ubiquitous protein unaltered.PI3K stands as one of the most promising targets for pharmaceutical intervention of cancer.[14]
