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DeepGlue

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Deep mutational scanning of target protein resistance to molecular glues

Interactions between proteins and small molecules are rich in nature – across organisms, tissues and cellular contexts they underly crucial biological functions in health and disease. One class of small biochemicals, molecular glu... ver más

31/01/2026

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165K€

Presupuesto del proyecto: 165K€

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FUNDACIO PRIVADA CENTRE DE REGULACIO GENOMICA Otras actividades deportivas asociacion

TRL 4-5 | 50K€

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Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2023-04-19

HORIZON-MSCA-2022-PF-01-01: MSCA Postdoctoral Fellowships 2022 ExpectedOutcome:

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Duración del proyecto: 33 meses Fecha Inicio: 2023-04-19
Fecha Fin: 2026-01-31

Líder del proyecto

FUNDACIO PRIVADA CENTRE DE REGULACIO GENOMICA Otras actividades deportivas asociacion

TRL 4-5 | 50K€

Presupuesto del proyecto 165K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Interactions between proteins and small molecules are rich in nature – across organisms, tissues and cellular contexts they underly crucial biological functions in health and disease. One class of small biochemicals, molecular glues (MGs), can selectively induce de novo protein-protein dimerization. Particularly in the context of targeted protein inhibition and degradation, MGs are praised as clinical alternatives to treating diseases driven by proteins that are otherwise pharmacologically intractable. Prominent examples like rapamycin, a MG used in the therapy of kidney tumours, illustrate a key research challenge, however: up until now, most MGs have been discovered by chance. Our limited understanding of their biophysical characteristics prevents us from rationally designing MGs, and from tracing drug resistance mechanisms by target proteins’ mutational escape during cancer evolution. Here, I propose a scalable experimental strategy to determine the binding profiles of MGs to thousands of target protein mutants in parallel. To perform comparisons of the biophysical impact of mutations on distinct MG mechanisms, I have three major aims: 1.) to develop a deep mutational scanning assay to quantify MG-protein-protein complexation, 2.) to produce the first global atlas of resistance mutations for a classic MG system – rapamycin in complex with MTOR and FKBP12, and 3.) to characterise ABA, a plant hormone which induces heterodimer formation by extensive structural remodelling of only one of its target proteins. DeepGlue will take place under the experienced supervision of Prof. Ben Lehner (CRG Barcelona), whose group has pioneered the use of deep mutagenesis to understand protein structures, dynamics and interactions. Within this environment, my action will be uniquely positioned to transcend the dynamic fields of Chemical Biology, Protein Biophysics and Cancer Evolution – aspiring to deliver fundamental insights that ultimately shape new and better therapies.

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