title: Discovery of small molecule CXCR4 antagonists.
abstract: In light of a proposed molecular mechanism for the C-X-C chemokine receptor type 4 (CXCR4) antagonist 1 (AMD3100), a template with the general structure 2 was designed, and 15 was identified as a lead by means of an affinity binding assay against the ligand-mimicking CXCR4 antagonist 3 (TN14003). Following a structure-activity profile around 15, the design and synthesis of a series of novel small molecular CXCR4 antagonists led to the discovery of 32 (WZ811). The compound shows subnanomolar potency (EC50 = 0.3 nM) in an affinity binding assay. In addition, when subjected to in vitro functional evaluation, 32 efficiently inhibits CXCR4/stromal cell-derived factor-1 (SDF-1)-mediated modulation of cyclic adenosine monophophate (cAMP) levels (EC50 = 1.2 nM) and SDF-1 induced Matrigel invasion (EC50 = 5.2 nM). Molecular field topology analysis (MFTA), a 2D quantitative structure-activity relationship (QSAR) approach based on local molecular properties (Van der Waals radii (VdW), atomic charges, and local lipophilicity), applied to the 32 series suggests structural modifications to improve potency.
authors.affiliation: Department of Chemistry, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhan
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liang
authors.forename: Aizhi
authors.initials: A
authors.lastname: Zhu
authors.forename: Serdar
authors.initials: S
authors.lastname: Kurtkaya
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D003094:Collagen; D000242:Cyclic AMP / Q000378:metabolism; D004338:Drug Combinations; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007797:Laminin; D008958:Models, Molecular; D009361:Neoplasm Invasiveness; D011509:Proteoglycans; D021281:Quantitative Structure-Activity Relationship; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D001596:Benzylamines; D054377:Chemokine CXCL12; D004338:Drug Combinations; D007797:Laminin; C525466:N,N'-di-2-pyridinyl-1,4-benzenedimethanamine; D011509:Proteoglycans; D019718:Receptors, CXCR4; C059485:matrigel; D003094:Collagen; D000242:Cyclic AMP