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ISRN Molecular Biology
Volume 2012 (2012), Article ID 823875, 9 pages
Research Article

Functional Characterization of a Small-Molecule Inhibitor of the DKK1-LRP6 Interaction

1Pharmacology Department, Sienabiotech S.p.A, Strada del Petriccio e Belriguardo 35, 53100 Siena, Italy
2Dipartimento di Biotecnologie, Università Degli Studi di Siena, Via Fiorentina 1, 53100 Siena, Italy
3High-throughput Screening Unit, Center for Genomic Regulation, Dr. Aiguader, 88, 08003 Barcelona, Spain

Received 13 September 2011; Accepted 4 October 2011

Academic Editors: D. Christophe, A. Maucuer, and A. J. Molenaar

Copyright © 2012 Sara Iozzi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.