Descripción del proyecto
Una plataforma análisis de la actividad de proteínas para el descubrimiento de fármacos
El triángulo oncogénico LIN28/HMGA2/IGF2BP1 es un grupo oncogénico de autopromoción de proteínas implicadas en muchos cánceres. El análisis proteico basado en la actividad de los residuos de cisteína se ha utilizado de forma eficaz para analizar el panorama de las cisteínas reactivas en un fenotipo concreto, lo que ha conllevado el descubrimiento de nuevas dianas terapéuticas y la modificación farmacológica de las dianas no modulables. El proyecto financiado con fondos europeos ABPP-PROTDRUG caracterizará la influencia de las proteínas LIN28/HMGA2/IGF2BP1 sobre el panorama celular de las cisteínas reactivas, centrándose en el cáncer de ovario y en el de hígado. Su objetivo principal es utilizar la química de marcaje de cisteína e ingeniería de proteínas para convertir en un arma las proteínas de interacción del triángulo oncogénico LIN28/HMGA2/IGF2BP1 como fármacos proteicos a través de terapias de proximidad.
Objetivo
Cancer remains one of the most prevalent diseases worldwide and new therapeutic targets are highly sought. The oncogenic triangle LIN28/HMGA2/IGF2BP1 is a self-promoting pro-tumorigenic group of proteins with relevant roles in many cancers that antagonize the let-7 family of miRNAs, which possess anti-tumorigenic roles.
Activity-based protein profiling applied to the measurement of cysteine reactivity profiles has been efficiently used to profile the landscape of ligandable cysteines in a given phenotype, which in turn has allowed the discovery of novel therapeutic targets in relevant disease phenotypes and the pharmacological modulation of targets previously described as undruggable.
Our approach will characterize the influence of the LIN28/HMGA2/IGF2BP1 proteins in the cellular landscape of ligandable cysteines, focusing on liver and ovarian cancer. Additional protein interacting partners to the oncogenic triangle will be identified and validated as novel anti-tumor targets. Variations in the probes used will allow the established methodology to be adapted to other entities like serine hydrolases, well known players in cancer and metastasis, or sulfenic acids, oxidized cysteines known to take part in redox control of the cellular environment.
Cysteine labeling chemistries and protein engineering will be used to weaponize LIN28/HMGA2/IGF2BP1 and their protein interactors against the oncogenic triangle as “protein drugs” via proximity-enabled reactive therapeutics, where reactive aminoacids are introduced in a native protein structure to allow a transient non-covalent interaction to be stabilized by formation of a permanent covalent bond. This approach is at the frontline of novel therapeutic methodologies and its application will restore the levels and function of let-7 miRNAs and their anti-tumor properties.
The outcome of this project will establish a powerful platform to weaponize transient non-covalent interactions as innovative therapeutic modulators.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinador
CB2 1TN Cambridge
Reino Unido