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

Projektbeschreibung

Ein neuer Ansatz für die Arzneimittelentwicklung bei Krebszielen

Die meisten niedermolekularen Arzneimittel gegen Proteine zielen in der Regel auf eine regulatorische Einheit oder das aktive Zentrum eines Enzyms ab. Es gibt jedoch molekulare Ziele, bei denen diese Strategie nicht anwendbar ist. Das EU-finanzierte Projekt E3glueRBP schlägt vor, dieses Problem durch den Einsatz kleiner Moleküle zu lösen, die eine Interaktion zwischen zwei Proteinen auslösen und den Abbau des krankheitsassoziierten Ziels bewirken. Das Forschungsteam wird eine Plattform entwickeln, die computergestützte und biochemische Methoden nutzt, um solche Proteindomänen vorherzusagen und geeignete molekulare Inhibitoren zu entwickeln. Die Projektergebnisse werden die Entwicklung von Krebsmedikamenten voranbringen und die gegenwärtigen therapeutischen Möglichkeiten erweitern.

Ziel

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.