title: Novel guanide-substituted compounds bind to CXCR4 and inhibit breast cancer metastasis.
abstract: CXCR4 has been shown to be overexpressed on breast cancer cells including the human MDA-MB-231 cell line. Cancer cells overexpressing the CXCR4 receptor are capable of undergoing metastasis to organs expressing high levels of CXCL12. We have synthesized numerous guanide, biguanide, phenylguanide, and naphthylguanide compounds that bind to CXCR4 at the CXCL12-binding site and thus should prevent CXCR4-facilitated cancer metastasis. The novel compounds presented here were tested for CXCR4 affinity, toxicity, receptor activation, and for their ability to prevent breast cancer metastases. Three of the compounds bound to CXCR4 at IC50 values of 0.06-0.2 μmol/l, with no associated cell toxicity or receptor activation at these concentrations. These high CXCR4 affinity compounds also showed inhibition of in-vitro wound migration. They were then tested in an in-vivo mouse breast cancer lung colony model. All of these compounds showed reductions in the number of MDA-MB-231 lung metastases compared with mock-treated control mice without evidence of cardiac, liver, or kidney toxicity in treated mice.
authors.affiliation: Departments of aChemistry and Biochemistry bMicrobiology, Montana State University, Bozeman, Montana, USA.
authors.forename: Joyce B
authors.initials: JB
authors.lastname: Shepard
authors.forename: Royce A
authors.initials: RA
authors.lastname: Wilkinson
authors.forename: Jean R
authors.initials: JR
authors.lastname: Starkey
authors.forename: Martin
authors.initials: M
authors.lastname: Teintze
mesh_terms: D000818:Animals; D001645:Biguanides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001645:Biguanides; D054377:Chemokine CXCL12; D006146:Guanidines; D019718:Receptors, CXCR4