Protein Kinases
Unlike any other proteomics company, Kinexus has chosen from its inception to focus on protein kinases and their intracellular signalling networks, which we refer to as "kineomes," although others have used the term “kinomes.” Proteins kinases are encoded by one of the largest classes of genes in the human genome, and they are the major mediators of communications in the information highways that operate inside of cells.
Protein kinases catalyze a chemical reaction in which the gamma phosphate group is transferred from the molecule adenosine triphosphate (ATP) to a recipient protein that acts as a substrate. This phosphorylation event commonly regulates the catalytic activity or other functions of target proteins or their destruction by proteases.
The human genome appears to encode 538 protein kinases in addition to many pseudo-protein kinase genes, and these have been subclassified into at least 10 families. There may well be additional protein kinases that remain to be identified. Protein kinases are readily recognized, because they feature characteristic amino acid sequences (approximately 16 that form subdomains) that distinguish these enzymes from other proteins. Recent studies at Kinexus have revealed that the vast majority of these protein kinases in diverse eukaryotic species may have originally evolved from glutamine tRNA synthetase.
In the fly Drosophila melanogaster, 319 of its 13,338 genes encode protein kinases. In the worm Caenorhabditis elegans, 437 of its 18,266 genes specify protein kinases. In the genome of the yeast Saccharomyces cerevisiae, protein kinases represent the largest family of related genes (121 out of 6,144 yeast genes encode protein kinases). For all of these organisms, this translates to approximately 2% of the total genes corresponding to protein kinases. In the mustard plant Arabidopsis thaliana 1049 putative protein kinases of 25,706 genes encode putative protein kinases. This represented about 4% of that plant's genome. The ciliate Paramecium tetraurelia features even more, with 2600 protein kinases. Presently, over 10,000 kinase-like sequences from diverse species are available for analysis in public databases.
Approximately fifty of the hundred or so known genes that have been directly linked to induction of cancer (i.e. oncogenes) encode protein kinases. The remainder of the oncogenes specify proteins that either activate kinases or are phosphorylated by kinases. Although the findings are less direct, aberrant cell signalling through protein kinases has also been associated with cardiovascular disease, diabetes, inflammation, arthritis and other immune disorders, and neurological disorders such as Alzheimer's disease. Over 400 human diseases have been connected to protein kinases.
Protein kinases catalyze a chemical reaction in which the gamma phosphate group is transferred from the molecule adenosine triphosphate (ATP) to a recipient protein that acts as a substrate. This phosphorylation event commonly regulates the catalytic activity or other functions of target proteins or their destruction by proteases.
The human genome appears to encode 538 protein kinases in addition to many pseudo-protein kinase genes, and these have been subclassified into at least 10 families. There may well be additional protein kinases that remain to be identified. Protein kinases are readily recognized, because they feature characteristic amino acid sequences (approximately 16 that form subdomains) that distinguish these enzymes from other proteins. Recent studies at Kinexus have revealed that the vast majority of these protein kinases in diverse eukaryotic species may have originally evolved from glutamine tRNA synthetase.
In the fly Drosophila melanogaster, 319 of its 13,338 genes encode protein kinases. In the worm Caenorhabditis elegans, 437 of its 18,266 genes specify protein kinases. In the genome of the yeast Saccharomyces cerevisiae, protein kinases represent the largest family of related genes (121 out of 6,144 yeast genes encode protein kinases). For all of these organisms, this translates to approximately 2% of the total genes corresponding to protein kinases. In the mustard plant Arabidopsis thaliana 1049 putative protein kinases of 25,706 genes encode putative protein kinases. This represented about 4% of that plant's genome. The ciliate Paramecium tetraurelia features even more, with 2600 protein kinases. Presently, over 10,000 kinase-like sequences from diverse species are available for analysis in public databases.
Approximately fifty of the hundred or so known genes that have been directly linked to induction of cancer (i.e. oncogenes) encode protein kinases. The remainder of the oncogenes specify proteins that either activate kinases or are phosphorylated by kinases. Although the findings are less direct, aberrant cell signalling through protein kinases has also been associated with cardiovascular disease, diabetes, inflammation, arthritis and other immune disorders, and neurological disorders such as Alzheimer's disease. Over 400 human diseases have been connected to protein kinases.
If there are about one million human phosphorylation sites, then each protein kinase targets on average well over 1000 phosphosites. Consequently, it is easy to image how a defective kinase could have major deleterious effects on normal cellular operations, especially when many of the substrates of protein kinases are other kinases. Most phosphosites appear to be phosphorylated at multiple sites by distinct protein kinases. This permits integration of multiple signalling pathways into elaborate communication networks or webs.
Protein kinases are the largest family of related genes identified so far that encode enzymes with measurable catalytic activities that are suitable to screen for inhibitory drugs. Protein kinases are amongst the most meticulously investigated enzymes by researchers. There is a wealth of data about these enzymes that already serves as a solid foundation from which to build. The primary structures of over 538 human protein kinases are already known and the three-dimensional structures of over 60 different protein kinases have been elucidated. Extensive artificial mutagenesis of several protein kinases has been performed to establish detailed structure-function relationships. After the proteases, protein kinases represent the most attractive candidates for molecular modelling studies to design new drugs.
It is estimated that over 30% of the drug discovery efforts in pharmaceutical and biotech companies are directed towards finding and validating protein kinase inhibitors. We believe that this will increase to over 50% within the next 5 years. These kinase-focused drugs have demonstrated applications for treatment of a wide range of diseases including cancer, inflammation, diabetes, congestive heart failure, and neurological damage. At least 35 kinase-focused therapeutics have been approved for use by the US FDA and other regulatory agencies (i.e. Afatinib (Gilotrif), Avastin (Bevacizumab), Axitinib (Inlyta), Bosutinib (Bosulif), Cabozantinib (Cometriq), Celecoxib (Celebrex), Ceritinib (Zykadia), Crizotininb (Xalkori), Dabrafenib (Tafinlar), Dasatinib (Sprycel), Erbitux (Cetuximab), Erlotinib (Tarceva), Everolimus (Afinitor), Fasudil, Gefitinib (Iressa), Herceptin (Trastuzumab), Ibrutinib (Imbruvica), Imatinib (Gleevec), Lapatinib (Tykerb), Nilotinib (Tasigna), Pazopanib (Votrient), Ponatinib (Iclusig), Regorafenib (Stivarga), Ruxolitinib (Jakafi), Sirolimus (Rapamune, Rapamycin), Sorafenib (Nexavar), Sunitinib (Sutent), Temsirolimus (Torisel), Toceranib (Palladia), Tofacitinib (Xeljanz), Trametinib (Mekinist), Vandetanib (Caprelsa), Valproate, Vectibix (Panitumumab), and Vemurafenib (Zelboraf)). Many of these generate annual revenues exceeding US $1 billion. Over 150 more protein kinase inhibitors are currently in advanced clinical trials, and at least another 500 are in pre-clinical studies. The pharmaceutical industry has clearly come to fully recognize the protein kinase family as a rich source of therapeutic targets. Yet remarkably, most of the kinase drugs in the clinic appear to target only about 75 protein kinases. Consequently, the therapeutic potential of the broad majority of protein kinases remains to be investigated. The growing arsenal of protein kinases inhibitors will clearly have a profound impact on the treatment of human diseases. An exciting area of pharmaceutical research will involve identification of new applications for these kinase drugs for treatment of other disease indications. Kinexus is dedicated to facilitating this prospect.
Protein kinases are the largest family of related genes identified so far that encode enzymes with measurable catalytic activities that are suitable to screen for inhibitory drugs. Protein kinases are amongst the most meticulously investigated enzymes by researchers. There is a wealth of data about these enzymes that already serves as a solid foundation from which to build. The primary structures of over 538 human protein kinases are already known and the three-dimensional structures of over 60 different protein kinases have been elucidated. Extensive artificial mutagenesis of several protein kinases has been performed to establish detailed structure-function relationships. After the proteases, protein kinases represent the most attractive candidates for molecular modelling studies to design new drugs.
It is estimated that over 30% of the drug discovery efforts in pharmaceutical and biotech companies are directed towards finding and validating protein kinase inhibitors. We believe that this will increase to over 50% within the next 5 years. These kinase-focused drugs have demonstrated applications for treatment of a wide range of diseases including cancer, inflammation, diabetes, congestive heart failure, and neurological damage. At least 35 kinase-focused therapeutics have been approved for use by the US FDA and other regulatory agencies (i.e. Afatinib (Gilotrif), Avastin (Bevacizumab), Axitinib (Inlyta), Bosutinib (Bosulif), Cabozantinib (Cometriq), Celecoxib (Celebrex), Ceritinib (Zykadia), Crizotininb (Xalkori), Dabrafenib (Tafinlar), Dasatinib (Sprycel), Erbitux (Cetuximab), Erlotinib (Tarceva), Everolimus (Afinitor), Fasudil, Gefitinib (Iressa), Herceptin (Trastuzumab), Ibrutinib (Imbruvica), Imatinib (Gleevec), Lapatinib (Tykerb), Nilotinib (Tasigna), Pazopanib (Votrient), Ponatinib (Iclusig), Regorafenib (Stivarga), Ruxolitinib (Jakafi), Sirolimus (Rapamune, Rapamycin), Sorafenib (Nexavar), Sunitinib (Sutent), Temsirolimus (Torisel), Toceranib (Palladia), Tofacitinib (Xeljanz), Trametinib (Mekinist), Vandetanib (Caprelsa), Valproate, Vectibix (Panitumumab), and Vemurafenib (Zelboraf)). Many of these generate annual revenues exceeding US $1 billion. Over 150 more protein kinase inhibitors are currently in advanced clinical trials, and at least another 500 are in pre-clinical studies. The pharmaceutical industry has clearly come to fully recognize the protein kinase family as a rich source of therapeutic targets. Yet remarkably, most of the kinase drugs in the clinic appear to target only about 75 protein kinases. Consequently, the therapeutic potential of the broad majority of protein kinases remains to be investigated. The growing arsenal of protein kinases inhibitors will clearly have a profound impact on the treatment of human diseases. An exciting area of pharmaceutical research will involve identification of new applications for these kinase drugs for treatment of other disease indications. Kinexus is dedicated to facilitating this prospect.
515 Known Protein Kinases Poster
Download a pdf poster produced by Kinexus of the 515 known human protein kinases, their evolutionary relationships, domain structures and phosphorylation sites. Contact Kinexus at info@kinexus.ca if you would like a printed copy of this 26 x 35 inch full colour glossy poster.