title: Development of a unique small molecule modulator of CXCR4.
abstract: BACKGROUND
  Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute and plays a major role in the morbidity and mortality of cancer. Inflammation is crucial for malignant tumor transformation and survival. Thus, blocking inflammation is expected to serve as an effective cancer treatment. Among anti-inflammation therapies, chemokine modulation is now beginning to emerge from the pipeline. CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 (CXCL12) interaction and the resulting cell signaling cascade have emerged as highly relevant targets since they play pleiotropic roles in metastatic progression. The unique function of CXCR4 is to promote the homing of tumor cells to their microenvironment at the distant organ sites.
  
  
  RESULTS
  We describe the actions of N,N'-(1,4-phenylenebis(methylene))dipyrimidin-2-amine (designated MSX-122), a novel small molecule and partial CXCR4 antagonist with properties quite unlike that of any other reported CXCR4 antagonists, which was prepared in a single chemical step using a reductive amination reaction. Its specificity toward CXCR4 was tested in a binding affinity assay and a ligand competition assay using (18)F-labeled MSX-122. The potency of the compound was determined in two functional assays, Matrigel invasion assay and cAMP modulation. The therapeutic potential of MSX-122 was evaluated in three different murine models for inflammation including an experimental colitis, carrageenan induced paw edema, and bleomycin induced lung fibrosis and three different animal models for metastasis including breast cancer micrometastasis in lung, head and neck cancer metastasis in lung, and uveal melanoma micrometastasis in liver in which CXCR4 was reported to play crucial roles.
  
  
  CONCLUSIONS
  We developed a novel small molecule, MSX-122, that is a partial CXCR4 antagonist without mobilizing stem cells, which can be safer for long-term blockade of metastasis than other reported CXCR4 antagonists.
authors.affiliation: Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liang
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Zhan
authors.forename: Aizhi
authors.initials: A
authors.lastname: Zhu
authors.forename: Younghyoun
authors.initials: Y
authors.lastname: Yoon
authors.forename: Songbai
authors.initials: S
authors.lastname: Lin
authors.forename: Maiko
authors.initials: M
authors.lastname: Sasaki
authors.forename: Jan-Michael A
authors.initials: JM
authors.lastname: Klapproth
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Hans E
authors.initials: HE
authors.lastname: Grossniklaus
authors.forename: Jianguo
authors.initials: J
authors.lastname: Xu
authors.forename: Mauricio
authors.initials: M
authors.lastname: Rojas
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Voll
authors.forename: Mark M
authors.initials: MM
authors.lastname: Goodman
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.forename: C Chris
authors.initials: CC
authors.lastname: Yun
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Hyunsuk
authors.initials: H
authors.lastname: Shim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D003198:Computer Simulation; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D005355:Fibrosis / Q000139:chemically induced / Q000188:drug therapy; D006258:Head and Neck Neoplasms / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008545:Melanoma / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008958:Models, Molecular; D011485:Protein Binding; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014604:Uveal Neoplasms / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; C573792:N,N'-(1,4-phenylenebis(methylene))dipyrimidin-2-amine; D011743:Pyrimidines; D019718:Receptors, CXCR4