Discovery of new small molecules inhibiting 67 kDa laminin receptor interaction with laminin and cancer cell invasion
PDF | HTML | Supplementary Files | How to cite
Metrics: PDF 1520 views | HTML 2682 views | ?
Ada Pesapane1, Carmen Di Giovanni2, Francesca Wanda Rossi1, Daniela Alfano3, Luigi Formisano4, Pia Ragno5, Carmine Selleri6, Nunzia Montuori1, Antonio Lavecchia2
1Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
2Department of Pharmacy, Drug Discovery Laboratory, University of Naples Federico II, Naples, Italy
3Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy
4Department of Science and Technology, University of Sannio, Benevento, Italy
5Department of Chemistry, University of Salerno, Salerno, Italy
6Department of Medicine and Surgery, University of Salerno, Salerno, Italy
Nunzia Montuori, e-mail: [email protected]
Keywords: laminin receptor, small molecules, laminin, cell adhesion
Received: March 06, 2015 Accepted: May 18, 2015 Published: May 29, 2015
The 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential.
We used structure-based virtual screening (SB-VS) to search for 67LR inhibitory small molecules, by focusing on a 37LRP sequence, the peptide G, able to specifically bind LM. Forty-six compounds were identified and tested on HEK-293 cells transfected with 37LRP/67LR (LR-293 cells). One compound, NSC47924, selectively inhibited LR-293 cell adhesion to LM with IC50 and Ki values of 19.35 and 2.45 μmol/L.
NSC47924 engaged residues W176 and L173 of peptide G, critical for specific LM binding. Indeed, NSC47924 inhibited in vitro binding of recombinant 37LRP to both LM and its YIGSR fragment. NSC47924 also impaired LR-293 cell migration to LM and cell invasion.
A subsequent hierarchical similarity search with NSC47924 led to the identification of additional four compounds inhibiting LR-293 cell binding to LM: NSC47923, NSC48478, NSC48861, and NSC48869, with IC50 values of 1.99, 1.76, 3.4, and 4.0 μmol/L, respectively, and able to block in vitro cancer cell invasion.
These compounds are promising scaffolds for future drug design and discovery efforts in cancer progression.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.