PI3K-selective inhibitors

Most 8-selective PI3K inhibitors are derived from IC87114 26, which has an IC50 of 130 nM against PI3K8 and 100-fold selectivity over the a, (3, and y isoforms [99,100], and showed oral efficacy in a neutrophil-driven model of inflammatory arthritis [101]. 

Mark Spyvee, Lynn D. Hawkins and Sally T. Ishizaka 

Frontier Product Creation Unit, 4 Corporate Drive, Andover, MA 01810, USA 

Annual Reports in Medicinal Chemistry, Volume 45 ISSN 0065-7743, DOI 10.1016/S0065-7743(10)45012-5 

Consistent with their role as immune receptors, each human TLR is expressed by at least one subset of myeloid cells (MCs) or lymphocytes [7,8]. TLRs are also present on stromal elements like endothelium particularly after local inflammatory stimulus [9-11]. These distribution patterns can determine the physiological consequences of stimulation or antagonism, and affect the balance of toxicity versus therapeutic effect. Another consideration for medicinal chemistry is subcellular localization of TLRs. While most are expressed on the cell surface, some (TLRs 3,7,8, and 9) can localize to endosomes where they survey ingested material for ligands, so drug access to this compartment can be crucial when targeting these TLRs [12]. 

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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... 

The probes of this type were shown to selectively label at least 75% of human kinases in crude cell lysates, thus demonstrating their selectivity and promiscuity for kinases [101]. As a follow up, the labeled kinases were subjected to proteolytic digestion, and the biotinylated peptides purified on avidin beads and analyzed by LC-MS/MS. This analysis demonstrated that the site of probe labeling was indeed the conserved active-site lysine as predicted. In contrast to the promiscuity demonstrated by the acyl phosphate probes, several selective covalent inhibitors of protein kinases have been used as ABPP probes. Wortmannin is a natural product derived from the fungus Penicillium funiculosum. It is a potent and specific covalent inhibitor of phosphoinositide 3-kinase (PI3K) and the PI3K-related kinase (PIKK) families [102, 103]. The use of natural products in relation to ABPP is covered by Breinbauer et al. [104]. 

Cell cycle arrest, apoptosis, cell proliferation, and cell differentiation are all mediated through signal transduction processes and appeared to be important executive targets for the operation of cancer chemoprevention. Several transducer proteins, such as cdks, cyclins, cdk inhibitors, ROS, cytochrome c, caspases, PARR Bcl-2, Bax, p53, c-jun, c-fos, c-myc, PKC, PKB, PI3K, MARK, NFkB, IKK, etc. are involved in these important cellular functions. Effects of the above mentioned phytopolyphenols on the activities of these transducer proteins were investigated by our laboratory and others, and the results will be selectively described and discussed. 

Doukas, J., Wrasidlo, W., Noronha, G., Dneprovskaia, E., Hood, J., Soil, R. Isoform-selective PI3K inhibitors as novel therapeutics for the treatment of acute myocardial infarction. Biochem. Soc. Trans. 2007, 35, 204-206. 

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