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E3-hijacking molecular glues of RNA binding protein IGF2BP1 in ovarian cancer

Project description

A novel drug design approach against cancer targets

Most small-molecule drugs against proteins usually target a regulatory moiety or the enzymatic active centre. However, there are molecular targets where this strategy cannot be implemented. The EU-funded E3glueRBP project proposes to address this issue through small molecules that induce interaction between two proteins and cause degradation of the disease-associated target. The team will develop a platform that utilises computational and biochemical methods to predict such protein domains and design appropriate molecular inhibitors. Project results will advance the field of cancer drug development and expand current therapeutic opportunities.

Objective

Conventional therapeutic strategy entails developing small molecules to occupy enzymatically active or regulatory pockets of the target protein, and further inhibit its biochemical activity. However, many disease-relevant proteins, such as RAS, MYC, or b-catenin, lack manageable druggable cavities. Bernardes and colleagues have raised a novel concept to overcome this limitation, named “molecular glues”, in which small molecules induce de-novo interactions between two proteins to modulate protein function. Molecular glues appeared as an elegant tool for targeted protein degradation, allowing simultaneous recruitment of a ubiquitin E3 ligase and the protein to be ubiquitinated. Notably, the potent anti-cancer drugs thalidomide, lenalidomide and pomalidomide (known as IMiDs for immuno-modulatory drugs), are the most prominent example of such E3-hijacking molecular glues, that exert their therapeutic effects through induced degradation of key efficacy targets. Building on these promising observations, herein I propose a designed platform that can rationally identify synthetic chemical matter to induce selective protein dimerization and induce disease-relevant protein ubiquitination and degradation – using ubiquitin E3 ligase and RNA binding protein IGF2BP1 as a proof-of-concept in ovarian carcinoma cells. The identification of complementary interfaces for drug-induced interactions will be achieved by computational prediction, protein-protein interaction assays, and a set of novel biochemical assays, together with high-throughput screening and structure-informed chemical optimization. This proposal will deliver a multi-layered technology to successfully design and validate novel molecular glues in a rational and generalizable way, to revolutionize current inhibitor-centric paradigms in cancer drug development and pharmacology. The strategy can be further transposed to other protein classes in different cancer types, and open an array of new therapeutic opportunities.

Call for proposal

H2020-WF-2018-2020

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Sub call

H2020-WF-03-2020

Coordinator

INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Net EU contribution
€ 159 815,04
Address
AVENIDA PROF EGAS MONIZ
1649 028 Lisboa
Portugal

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SME

The organization defined itself as SME (small and medium-sized enterprise) at the time the Grant Agreement was signed.

Yes
Region
Continente Área Metropolitana de Lisboa Área Metropolitana de Lisboa
Activity type
Research Organisations
Links
Total cost
€ 159 815,04