Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.2 (PDK1)
 2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PI3K is an important node regulating the signaling of several essential biological processes. PI3K catalyzes the phosphorylation in position 3 of the inositol ring of phosphatidyl-inositide producing important lipid second messengers. The products of PI3K activity recruit PDK1 and AKT Ser/Thr kinases to the plasma membrane where they get activated transducing a potent proliferative and anti-apoptotic signal to the cell. PI3K is activated by growth factors, insulin and GPCR activation. Furthermore, PI3K can be activated by direct binding to oncogenic Ras proteins. PI3K is commonly altered in human cancers by point activating mutations or by amplification. Furthermore, other proteins of the route are also altered in human tumors (such as phosphatase and tensin homolog in chromosome 10 or human EGF receptor 2) providing constitutive activation of PI3K. The evidence indicates that the PI3K pathway is a potential target for cancer chemotherapy. Indeed, many companies and academic laboratories have initiated a variety of approaches to inhibit the PI3K pathway at different points. In this work, we review the targeting of PI3K protein for therapeutical intervention.
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PMID:Novel inhibitors of the PI3K family. 1958 91

The group of AGC protein kinases includes more than 60 protein kinases in the human genome, classified into 14 families: PDK1, AKT/PKB, SGK, PKA, PKG, PKC, PKN/PRK, RSK, NDR, MAST, YANK, DMPK, GRK and SGK494. This group is also widely represented in other eukaryotes, including causative organisms of human infectious diseases. AGC kinases are involved in diverse cellular functions and are potential targets for the treatment of human diseases such as cancer, diabetes, obesity, neurological disorders, inflammation and viral infections. Small molecule inhibitors of AGC kinases may also have potential as novel therapeutic approaches against infectious organisms. Fundamental in the regulation of many AGC kinases is a regulatory site termed the "PIF-pocket" that serves as a docking site for substrates of PDK1. This site is also essential to the mechanism of activation of AGC kinases by phosphorylation and is involved in the allosteric regulation of N-terminal domains of several AGC kinases, such as PKN/PRKs and atypical PKCs. In addition, the C-terminal tail and its interaction with the PIF-pocket are involved in the dimerization of the DMPK family of kinases and may explain the molecular mechanism of allosteric activation of GRKs by GPCR substrates. In this review, we briefly introduce the AGC kinases and their known roles in physiology and disease and the discovery of the PIF-pocket as a regulatory site in AGC kinases. Finally, we summarize the current status and future therapeutic potential of small molecules directed to the PIF-pocket; these molecules can allosterically activate or inhibit the kinase as well as act as substrate-selective inhibitors. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012).
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PMID:AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases. 2352 93