Development of dual-targeting epigenetic modulators for polypharmacology-based cancer therapy

Descripción del proyecto

Estrategia multidiana para superar la resistencia a los tratamientos antineoplásicos

La aparición y el desarrollo del cáncer se ven afectados por muchos parámetros, como la genética, el medio ambiente y los factores epigenéticos. Por ello, los fármacos que se dirigen simultáneamente a múltiples enzimas epigenéticas pueden ser una estrategia terapéutica prometedora para superar la resistencia a los tratamientos antineoplásicos. Partiendo de esta premisa, el equipo del proyecto financiado con fondos europeos EpiPolyPharma está desarrollando nuevas moléculas dirigidas a la metilación y acetilación de proteínas (comunes en las vías epigenéticas). En concreto, los investigadores están estudiando las enzimas que cooperan en diferentes vías de forma simultánea para contrarrestar el crecimiento tumoral. Los inhibidores más prometedores se evaluarán en ensayos celulares y por sus efectos en la regulación de la transcripción de los genes del cáncer, por lo que se espera obtener instrumentos personalizados adicionales para combatir el cáncer y la farmacorresistencia relacionada con él.

Objetivo

Cancer is a multifactorial disorder involving different genetic and epigenetic alterations. Since epigenetic modifications are brought about by multiple enzymes working synergistically, multitargeting compounds may be particularly effective to acutely interfere with aberrant processes. The simultaneous inhibition of two or more enzymes by a single molecule provides improved therapeutic efficacy compared to single-target inhibitors, along with reduced insurgence of drug resistance.
Through this project, I aim at developing novel therapeutics targeting protein (de)methylation and (de)acetylation for application in cancer therapy. I will synthesise and evaluate hybrid molecules inhibiting two enzymes at the same time. I will develop two classes of compounds targeting the Lysine-specific histone demethylase 1A (LSD1) and either Protein arginine N-methyltransferase 5 (PRMT5) or Histone deacetylases 1-2 (HDAC1-2). These enzymes cooperate in different pathways that lead to cancer insurgence and progression, hence dual targeting represents a successful strategy to counteract tumour growth.
To achieve the outlined aims, I will employ a multidisciplinary approach requiring the fusion of knowledge and tools from medicinal chemistry, biochemistry, biophysics, molecular and cell biology. Through the employment of cutting-edge synthetic approaches, I will prepare LSD1/PRMT5 and LSD1/HDAC1-2 inhibitors which will be assessed through multiple biochemical and biophysical assays. I will also employ native mass spectrometry to investigate their mode of action in the context of the multi-protein complexes formed by the protein targets. The most promising inhibitors will be evaluated in cellular assays to assess their anticancer properties and their effects on transcriptional regulation.
This project will open innovative avenues for personalised therapies and provide additional weapons to overcome drug resistance, along with adding new knowledge on the epigenetic mechanisms of cancer.