Chemical rewiring of E3 ubiquitin ligases as a generalizable therapeutic approach

Información del proyecto

TrickE3

Identificador del acuerdo de subvención: 101040046

DOI

10.3030/101040046

Fecha de la firma de la CE 14 Febrero 2022

Fecha de inicio 1 Marzo 2022

Fecha de finalización 28 Febrero 2027

Financiado con arreglo a

• European Research Council (ERC)

Coste total

€ 1 499 625,00

Aportación de la UE

€ 1 499 625,00

Coordinado por

FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA)
Spain

Periodic Reporting for period 1 - TrickE3 (Chemical rewiring of E3 ubiquitin ligases as a generalizable therapeutic approach)

Período documentado: 2022-03-01 hasta 2024-08-31

Resumen del contexto y de los objetivos generales del proyecto

Despite great progress in therapeutic drug development, ~ 90% of all human proteins remain beyond the reach of conventional drug discovery (inhibitors), leaving some of the most compelling targets inaccessible to therapeutic development. Traditional drug design focuses mainly on finding and blocking specific pockets of therapeutically relevant proteins to stop their activity.
Our TrickE3 project focuses on the systematic development and discovery of a promising type of drugs referred to as “monovalent degraders”. These drugs can bind to a protein of therapeutic interest and recruit the natural cellular degradation machinery (E3 ligases) to remove it. This approach makes it possible to eliminate proteins that were previously considered inaccessible and thus provides new perspectives for the treatment of a wide range of diseases. Monovalent degraders also have highly desirable physicochemical properties, which could in principle help them reach clinical practice.

Despite the enormous potential of this type of pharmacology, the few that are available have been discovered by chance, without following a rational strategy. The TrickE3 project has the ambitious goal of changing this paradigm and systematizing both the design of and search for these drugs. Although applicable to many diseases, as proof of principle, we focus on the chemical rewiring of E3s expressed in pancreatic ductal adenocarcinoma (PDAC) due to the imperative need for treatments. We intend to prospectively identify monovalent degraders (i) of specific vulnerabilities, and (ii) to unlock new PDAC targets.

We hope that the methods we want to implement help to turn protein degradation into a generalizable therapeutic strategy. At the interface of chemical biology and cancer research, TrickE3 will be an instrumental resource to broaden drug discovery efforts and to empower other disciplines to chemically explore the degradation of relevant targets.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

In this first period of TrickE3, we have successfully established some of our intended cellular and computational approaches to identify monovalent degraders. In brief, we have delivered proof of concept that phenotypic and virtual drug screenings can deliver both, monovalent degraders with known mechanisms of action, but also compounds with novel unexpected working features. The engineering of additional reporters has been completed, unlocking more drug screens in the near future.

In addition, we unraveled new concepts around degrader resistance and how to overcome it. Conceptually, the loss of function of a broad E3 ligase regulator poses an advantageous mechanism to evade the action of a wide range of degraders (Barbosa et al., Angewandte Chemie, 2024). We conducted a target-agnostic chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. This comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the enzyme NQO1, which is highly overexpressed in our resistance models.
Mechanistically, we showed that inactivation of one particular E3 leads to NQO1 upregulation. Our findings motivate translational investigation via the chemical probe RBS-10 and similar molecules in cancer types with elevated NQO1.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

As our TrickE3 project progresses, we are uncovering fascinating mechanisms by which monovalent degraders prompt target destruction. Among these discoveries, one particularly intriguing revelation is that weak protein-protein interactions are prevalent in nature and may reflect the general tendency of proteins to undergo partner-selective contacts. In some cases, these weak interactions are nevertheless “drug-enhanceable”. We have demonstrated that the computational survey of these weak interactions could help rationalize monovalent degrader discovery. By leveraging the molecular insights from these discoveries, we are not only shedding light on the intricate workings of our proteome but also accelerating the generation of the next-generation therapeutics.