New molecules inspired on microbiota metabolites targeting cancer phenotypes

Abstract

In the past three decades, target-based drug discovery (TDD) has been the dominant approach to drug discovery. However, in recent years, there has been a renewed interest in phenotypic drug discovery (PDD) approaches, which allow to identify biologically active molecules in a physiologically relevant system, without needing to know the target protein a priori. In the present medicinal chemistry project, a PDD program will be addressed to identify new drug candidates. Human microbiota is a complex ecosystem of symbiotic microorganisms that play an important role in human health and disease. The crosstalk between the host and its microbiome occurs in part through the secretion of metabolites, which can regulate human proteins. Recent studies suggest the influence of the microbiota and its metabolites in several diseases, such as cancer, obesity, diabetes, immune system disorders, or neurological pathologies. In the context of cancer, various microbiota metabolites have been shown to play a major role in tumor protection. Therefore, these metabolites could represent an unexplored chemical space with important biological activities. In this work, we have developed new small molecules inspired on microbiota metabolites that could lead to novel therapeutic strategies for cancer treatment...En las últimas décadas, el descubrimiento de fármacos dirigidos a una diana terapéutica específica, target-based drug discovery (TDD), ha sido la estrategia predominante en la búsqueda de nuevos fármacos. Sin embargo, recientemente ha resurgido el interés por los programas basados en estudios fenotípicos, phenotypic drug dicovery (PDD), los cuales permiten identificar compuestos que inducen una respuesta biológica de interés sin la necesidad de conocer la diana molecular subyacente. Los ensayos fenotípicos proporcionan un enfoque menos sesgado para detectar moléculas capaces de regular una diana terapéutica y los compuestos identificados suelen tener un mayor impacto terapéutico in vivo. En este contexto, el presente proyecto de química médica se ha abordado mediante un programa de PDD enfocado al descubrimiento de nuevos fármacos antitumorales...