000341555 001__ 341555
000341555 005__ 20230827173317.0
000341555 0247_ $$2CORDIS$$aG:(EU-Grant)101107635$$d101107635
000341555 0247_ $$2CORDIS$$aG:(EU-Call)HORIZON-MSCA-2022-PF-01$$dHORIZON-MSCA-2022-PF-01
000341555 0247_ $$2originalID$$acorda_____he::101107635
000341555 035__ $$aG:(EU-Grant)101107635
000341555 150__ $$aDeep mutational scanning of target protein resistance to molecular glues$$y2024-02-01 - 2026-01-31
000341555 372__ $$aHORIZON-MSCA-2022-PF-01$$s2024-02-01$$t2026-01-31
000341555 450__ $$aDeepGlue$$wd$$y2024-02-01 - 2026-01-31
000341555 5101_ $$0I:(DE-588b)5098525-5$$2CORDIS$$aEuropean Union
000341555 680__ $$aInteractions 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.
000341555 909CO $$ooai:juser.fz-juelich.de:1010914$$pauthority:GRANT$$pauthority
000341555 909CO $$ooai:juser.fz-juelich.de:1010914
000341555 980__ $$aG
000341555 980__ $$aCORDIS
000341555 980__ $$aAUTHORITY