title: Functional Characterization of a Small-Molecule Inhibitor of the DKK1-LRP6 Interaction.
abstract: Background. DKK1 antagonizes canonical Wnt signalling through high-affinity binding to LRP5/6, an essential component of the Wnt receptor complex responsible for mediating downstream canonical Wnt signalling. DKK1 overexpression is known for its pathological implications in osteoporosis, cancer, and neurodegeneration, suggesting the interaction with LRP5/6 as a potential therapeutic target. Results. We show that the small-molecule NCI8642 can efficiently displace DKK1 from LRP6 and block DKK1 inhibitory activity on canonical Wnt signalling, as shown in binding and cellular assays, respectively. We further characterize NCI8642 binding activity on LRP6 by Surface Plasmon Resonance (SPR) technology. Conclusions. This study demonstrates that the DKK1-LRP6 interaction can be the target of small molecules and unlocks the possibility of new therapeutic tools for diseases associated with DKK1 dysregulation.
authors.affiliation: Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; Dipartimento di Biotecnologie, Università Degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Iozzi
authors.affiliation: Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Remelli
authors.affiliation: Dipartimento di Biotecnologie, Università Degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lelli
authors.affiliation: Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Diamanti
authors.affiliation: Dipartimento di Biotecnologie, Università Degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pileri
authors.affiliation: Dipartimento di Biotecnologie, Università Degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Bracci
authors.affiliation: Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy; High-throughput Screening Unit, Center for Genomic Regulation, Dr. Aiguader, 88, 08003 Barcelona, Spain.
authors.forename: Renza
authors.initials: R
authors.lastname: Roncarati
authors.affiliation: Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Caricasole
authors.affiliation: Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Bernocco