title: Discovery and characterization of novel small-molecule CXCR4 receptor agonists and antagonists.
abstract: The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 are involved in a large number of physiological processes including HIV-1 infectivity, inflammation, tumorigenesis, stem cell migration, and autoimmune diseases. While previous efforts have identified a number of CXCR4 antagonists, there have been no small molecule agonists reported. Herein, we describe the identification of a novel series of CXCR4 modulators, including the first small molecules to display agonist behavior against this receptor, using a combination of structure- and ligand-based virtual screening. These agonists produce robust calcium mobilization in human melanoma cell lines which can be blocked by the CXCR4-selective antagonist AMD3100. We also demonstrate the ability of these new agonists to induce receptor internalization, ERK activation, and chemotaxis, all hallmarks of CXCR4 activation. Our results describe a new series of biologically relevant small molecules that will enable further study of the CXCR4 receptor and may contribute to the development of new therapeutics.
authors.affiliation: The Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston IL, USA.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Department of Pharmacology, Northwestern University, Chicago IL, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Shum
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA.|Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago IL, USA.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.affiliation: Department of Pharmacology, Northwestern University, Chicago IL, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Miller
authors.affiliation: The Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston IL, USA.|Department of Pharmacology, Northwestern University, Chicago IL, USA.|Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago IL, USA.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Schiltz
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D055808:Drug Discovery; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D015394:Molecular Structure; D019718:Receptors, CXCR4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019380:Anti-HIV Agents; D019718:Receptors, CXCR4; D002118:Calcium