Phosphorylation of proteins, on their Serine, Threnine or Tyrosine residues, by protein kinases, constitute one of the most fundamental an universal post-translational control of cellular protein activity. Among the 518 human kinases, some are abnormally expressed or regulated in human cancers and constitute therapeutic targets. The american Food and Drug Administration (FDA) has already approved the marketing of 27 kinases inhibitor ( including 14 since 2013) principally in the course of carrying cancers treatments ( july 2015). Besides, more than 500 others kinases inhibitors are in clinical phase (www.brimr.or/PKI/PKIs.htm). It is important to note that since april 2015, the first prescriptions of Ibrance (Palbocidib, Pfizer Inc) are effective in the United States for the treatment of metastatic breast cancers. It is the first CDKs inhibitor (precisely CDK4 and 6) going on the market a class of historic enzymes for our screening platform KISSf ( Kinase Inhibitor Specialized Screening facility).
SCIENTIFIC EXPERTISE: FIRST AUTOMATED SCREENING IN 2001
KISSf is is a high throughput screening facility for the identification and of caracterization of news proteins kinases inhibitors. Following, the works led on the first stage of cellular division on sea urchins embryos and starfish oocytes, the team focused its efforts on several protein kinase families potentially relevant for the treatment of several human diseases such as cancer. Our research work describes the role of protein kinases involved in the mechanisms of cellular proliferation as well as the mode of action and the selectivity of their inhibitors. Among these kinases, the cycline-dependent kinases (CDKs) were widely studied because of their essential roles in biological processes and their implication in numerous pathologies. CDKs inhibitors have particular properties: on one hand, they trigged tumoral cell death by apoptosis ((by a mechanism involving Mcl-1 or others factors of survival) and on the others hand, they show protective effects towards neuronal healthy cells involving CDK5). These studies have allowed the identification, the optimization and the characterization of many protein kinase inhibitor families kinases such as: oloumocine, roscovitine, purvalanol, paullones, indirubines, hymenialdisine, meridianines, meriolines. The key molecule is the (R)-roscovitine actually in phase2b for the treatment of syndrome de Cushing (chronical hypercortisolisme ). The strategy followed by KISSf for the research of inhibitors of proteins kinases is to identify ATP mimetic compounds (type I inhibitors) able to bind the ATP pocket of the enzyme. The fact that there is structural variability on this particular site from a kinase to another makes it possible to find specific inhibitors. Chemical inhibitors characterized by KISSf are either potential new therapeutic molecules or tools for fundamental research to help understand the protein kinases cellular functions (chemical biology).
THE PANELS OF KINASES: THE OFFER OF KISSF
KISSf offers an analyse of biological effect of inhibitors with a flow of 2000 compounds/day on one kinase. The following kinases are available for analyse. Kinases “Research” (mitotic and necroptotics): (1)Hs_PLK1, (2)Hs_TLK1, (3)Hs_HASPIN, (4)Hs_AURKB, (5)Hs_RIPK3 The identified kinase inhibitors can be further analyzed on mammal cells by our research teams, part of the USR3151 CNRS / UPMC. CURRENT RESOURCES DEDICATED TO KINASES IN VITRO TESTS: Microtiter plate assay, incubation and reaction are performed using robots (MiniJANUS, PerkinElmer and Multidrop dispenser, ThermoScientific). Kinase assay is performed in the presence of radio-labeled ATP (33P) together with specific buffer and substrate for each kinase. The results are obtained by liquid scintillation counting coupled to an automated 96-well plate feeder (Top Count NXT, PerkinElmer).
KINASE INHIBITORS MARKET
Table identifying the different kinase inhibitors on the US market’s drug (approved by the Food and Drug Administration, FDA). Courtesy of Dr. Robert Roskoski Jr., Blue Ridge Institute for Medical Research in Horse Shoe, North Carolina USA.
If you want to analyse the bioactivity of your samples on KISSf screening facility please stick to the terms and conditions in the attached document. * For the submission of more than 96 compounds, please contact us (KISSf@sb-roscoff.fr). ** Please send no more than 5 mg of chemical compound in 1.5ml tube with screw cap and w/o parafilm.