Discovery of new small molecules inhibiting 67 kDa laminin receptor interaction with laminin and cancer cell invasion

• Published in: Oncotarget Vol. 6; no. 20; pp. 18116 - 18133
• Main Authors: Pesapane, Ada, Di Giovanni, Carmen, Rossi, Francesca Wanda, Alfano, Daniela, Formisano, Luigi, Ragno, Pia, Selleri, Carmine, Montuori, Nunzia, Lavecchia, Antonio
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 20.07.2015
• Subjects: Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Adhesion - drug effects; Cell Movement - drug effects; Computer Simulation; Computer-Aided Design; Dose-Response Relationship, Drug; Drug Discovery - methods; HEK293 Cells; Humans; Laminin - antagonists & inhibitors; Laminin - metabolism; Models, Molecular; Naphthols - chemistry; Naphthols - pharmacology; Neoplasm Invasiveness; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Protein Binding; Protein Conformation; Receptors, Laminin - antagonists & inhibitors; Receptors, Laminin - chemistry; Receptors, Laminin - metabolism; Research Paper; Ribosomal Proteins - antagonists & inhibitors; Ribosomal Proteins - chemistry; Ribosomal Proteins - metabolism; Signal Transduction - drug effects; Structure-Activity Relationship; Transfection; laminin; laminin receptor; cell adhesion; small molecules
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.4016

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.