Novel paradigms in drug discovery: Identification of new lead compounds for K-RAS+ colon cancer

DARIO R. BICHARA; LUCAS A. DEFELIPE; LORIS A. GURFINKIEL; ALBERTINA G. MOGLIONI; EDUARDO G. CAFFERATA; ADRIÁN G. TURJANSKI; SERGIO H. SIMONETTA

Congreso; 17th World Congress of Basic and Clinical Pharmacology; 2014

1008NOVEL PARADIGMS IN DRUG DISCOVERY:IDENTIFICATION OF NEW LEAD COMPOUNDS FOR KRAS+COLON CANCERBichara D., Defelipe L., Gurfinkiel L., Moglioni A., Cafferata E.G,Turjanski A., Simonetta S.Background: The standard process of drug development consists ofmultiple iterations of in vitro biochemical and cell-based assays, followedby in vivo studies in animal models and trials in humans. Thisproceeding takes 12?15 years and costs millions of dollars, but <1%of the developed drugs result in success. Much of the failure comes atthe level of animal testing, where problems with absorption, distribution,metabolism, excretion and toxicity are first assessed. This couldbe overcome using in vivo animal models at the initial stage of thispipeline. Two of the currently used organisms for this purpose are C.elegans and Zebrafish. These models allow conducting a low cost,high-throughput biological first assessment of a compound in a veryshort time. In our laboratory we are using this strategy together withstate of the art in silico processes and own-developed novel technologiesto discover small molecules with potential effect against K-RAS+colon cancer.Methods: First, molecular docking dedicated software was used tonarrow compound libraries of hundreds of thousands molecules targetingK-RAS. Then, the selected molecules were tested in a C. elegansmutant line harboring the K-RAS+ gene. Those molecules that showedactivity were tested in cell culture using a proliferation assay withcolon cancer K-RAS+ cells (LoVo). Finally, the remaining selectedmolecules are being tested in rodents at the moment, using nu/nu nudemice which were injected subcutaneously in right flank with LoVocells, thus developing tumors.Results: Using molecular docking we were able to extract, from a65,000 molecules library, 19 potential anti K-RAS+ colon cancerdrugs. The C. elegans screening of those molecules showed that fourof them prevent the K-RAS+ associated phenotype equal or better thana commercial MEK-1/2 inhibitor (U0126). Further experiments in cellculture assays demonstrated that two of them have anti proliferationactivity. Those two molecules are now being tested in mice.Conclusions: This novel procedure involving state of the art andown-developed technology and multi-species screening allows us tochange the paradigm of the drug discovery process by shortening timeand saving money in the identification of new lead compounds.