PROTEOLYSIS TARGETING CHIMERAS FOR TARGETED DEGRADATION OF PROTEIN KINASES REGULATING CIRCADIAN RHYTHM IN AD
Home institution: Alma Mater Studiorum University of Bologna – Italy (24 months)
Host institution: IMDEA Nanociencia – Spain (10 months)
PhD Enrolment #1: Alma Mater Studiorum University of Bologna – Italy
PhD Enrolment #2: Universidad Complutense de Madrid – Spain
Supervisor #1: Maria Laura Bolognesi
Supervisor #2: Valle Palomo
Intersectoral Secondment: Nostrum Biodiscovery – Spain
Objectives:
The BOMedCHem (https://site.unibo.it/medchembolab-bolognesi/en) lab at Department of Pharmacy and Biotechnology, University of Bologna, Italy, is looking to appoint a Marie Curie Research Fellow within a fixed-term project entitled “Proteolysis Targeting Chimeras for targeted degradation of protein kinases regulating circadian rhythm in AD”, funded by the Horizon Europe project TClock4AD. The doctoral candidate will work for two years in Italy (University of Bologna) and for 10 months in Spain (IMDEA Nanociencia) and will be involved in a 2-month secondment to a Spanish company (Nostrum Biodiscovery).
The main objective for DC1 is to execute a medicinal chemistry investigation that will exploit proteolysis targeting chimeras (PROTACs) to modulate kinases regulating circadian rhythm, as proteins of interest (POI). Specifically, the DC will exploit computational tools for structure and ligand-based design and will use the results to design molecules that have optimal modulation of the kinase of interest. Whenever possible the DC will interact with DC3 at NBD for modelling and DC5 for hit selection. In the PROTAC setting, the DC will investigate ligands for the binding of both the POI to be degraded and the E3 ligase. The two protein and binding entities will be investigated to identify optimal tethers. Then, the DC will evaluate POI degradation to critically verify the ability of non-toxic and permeable PROTACs (selected by DC5) to promote kinase degradation via the proteasome.
Expected outcomes:
The fellow is expected to generate breakthrough ideas in the assigned area of research, as well as to carry out research in line with the project plan. The fellow is also expected to contribute to dissemination and communication activities, besides actively collaborating within the TClock4AD network. This doctoral candidate will work closely with consortium partners at IMDEA and NBD (Spain).
