TheraGnosis. For therapy and diagnosis. Slow the traffic down, turn the lights up: new P-glycoprotein inhibitors to block drug efflux from cancer cells and spark imaging in early neurodegeneration diagnosis
Aree / Gruppi di ricerca
Partecipanti al progetto
- Guglielmo Stefano (Coordinatore/trice)
- Lazzarato Loretta (Docente)
Descrizione del progetto
Membri esterni:
Dr. Marialessandra CONTINO, Prof. Nicola A. COLABUFO (Universita’ degli Studi di Bari “A. Moro”)
Sponsor:
Università di Torino - www.unito.it
Description:
P-glycoprotein (P-gp) belongs to the ATP-Binding Cassette (ABC) transporter family and its expression by cancer cells is associated with multidrug resistance (MDR), which is a major cause of chemotherapeutic treatment failure in cancer therapy. Moreover a correlation between P-gp dysfunction in the Blood Brain Barrier (BBB) and early stage of Alzheimer’s disease (AD) and other amyloidopathies has been observed, due to a decreased P-gp mediated efflux of amyloid beta. On these bases, radiolabeled P-gp ligands can prove potent tools for early diagnosis of AD through the non invasive positron emission tomography (PET) technique.
The present proposal is aimed at covering an unmet need through the development of new potent P-gp inhibitors as diagnostic tools: indeed most PET tracers for P-gp investigated in humans so far are high-affinity P-gp substrates but their low brain uptake makes the assessment of alterations in P-gp function/expression very challenging.
Based on some P-gp inhibitors realized by the PI, belonging to the class of structurally correlated biphenyl substituted 6,7-dimethoxytetrahydroisoquinoline derivatives and having sub-micromolar to nanomolar activity, an ample structural modulation will be fulfilled exploiting the state-of-the-art medicinal chemistry techniques, in order to generate a chemical library of compounds. These new chemical entities will be evaluated in vitro for their potency, selectivity and P-gp interacting mechanism. Moreover the most relevant pharmacokinetic parameters (logP, pKa and apparent permeability (Papp) in Caco-2 cell line) and biological properties (P-gp activity and permeability assay in human BBB cells) will be evaluated, in order to identify from 1 to 5 potent and selective P-gp inhibitors with optimized pharmacokinetic profile suitable for application in PET for early AD diagnosis.
Collaboration:
Keywords: Alzheimer’s disease; Multi-drug Resistance (MDR); Pgp ligands; PET
Settori di ricerca ERC (European Research Council) interessati dal Progetto di Ricerca
LS7_3 Pharmacology, pharmacogenomics, drug discovery and design, drug therapy
Settori scientifico-disciplinari interessati dal Progetto di Ricerca
CHIM/08 Chimica farmaceutica