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An Activity-based Protein Profiling-supported Protein Therapeutic Drug discovery platform for the development of innovative anti-cancer therapies based on Lin28 inhibition

Project description

An activity-based protein-profiling platform for drug discovery

LIN28/HMGA2/IGF2BP1 comprises a self-promoting oncogenic group of proteins implicated in many cancers. Activity-based protein profiling of reactive cysteine residues has been efficiently used to profile the landscape of reactive cysteines in a given phenotype, resulting in the discovery of novel therapeutic targets and the pharmacological modification of targets previously described as undruggable. The EU-funded ABPP-PROTDRUG project will characterise the influence of the LIN28/HMGA2/IGF2BP1 proteins on the cellular landscape of reactive cysteines with a focus on liver and ovarian cancer. The main objective is to use cysteine labelling chemistry and protein engineering to weaponise protein interactors of the LIN28/HMGA2/IGF2BP1 oncogenic triangle as protein drugs via proximity-enabled reactive therapeutics.

Objective

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.

Coordinator

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Net EU contribution
€ 212 933,76
Address
TRINITY LANE THE OLD SCHOOLS
CB2 1TN Cambridge
United Kingdom

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Region
East of England East Anglia Cambridgeshire CC
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 212 933,76