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Precision medicine: GEF activators of the SOS family as therapeutic targets in Ras-dependent tumors

19th national competition for scientific and technical research

Precision Medicine and Cancer

Senior Researcher : Eugenio Santos de Dios

Research Centre or Institution : Instituto de Biología Molecular y Celular del Cáncer. Universidad de Salamanca-CSIC.

Abstract

The objectives proposed in this project focused on the search and characterization of inhibitors of the activation of Ras GTPases by their GEF activators of the SOS family. During the three years of the project, we have carried out three “screenings” with various compound libraries: 707 compounds from the collection of the NIH drug reuse program “NCATS- The Small Molecule Resource (SMR) compound library”; 500 compounds of marine origin from the company Biomar Microbial Technologies and 144 poisons of animal origin from the collection of Dr. Maria Ikonomopoulou (IMDEA, Madrid). From these screenings, we were able to isolate three inhibitors of Ras activation by SOS, two from Biomar and one from the NIH collection. For these compounds, the IC50 was calculated, being of the order of micromolar. In addition, they were tested in several lines of pancreatic and lung cancer, the types of cancer with the highest rate of Ras activation, being efficient in the inhibition of cell growth. Finally, these compounds were tested in healthy animals to analyze their toxicity, observing cardiotoxicity in the compound belonging to the NIH collection, but no toxicity was observed when the Biomar Microbial Technologies compounds were analyzed. The data obtained in these studies has been published in the journal “Biomolecules”: Fernández-Medarde A, et al. Anthraquinones as Inhibitors of SOS RAS-GEF Activity. Biomolecules. 2021 Jul 30;11(8):1128.

The inhibitors isolated in the screening have a high IC50 for clinical development. For this reason, our latest studies have focused on carrying out a new screening using lung cancer organoids derived from a Kras G12D mice that develop lung cancer spontaneously after a few months of life. We have fine-tuned the generation of organoids and carried out a first test of inhibition of their growth, obtaining two compounds with activity, which continue to be characterized..

 

Scientific Production
 
Magazine Articles 4
Communications at national conferences 4
Communications at international conferences 6

 

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