title: Discovery and computer aided potency optimization of a novel class of small molecule CXCR4 antagonists.
abstract: Amongst the chemokine signalling axes involved in cancer, chemokine CXCL12 acting on chemokine receptor CXCR4 is particularly significant since it orchestrates migration of cancer cells in a tissue-specific metastatic process. High CXCR4 tumour expression is associated with poor prognosis of lung, brain, CNS, blood and breast cancers. We have identified a new class of small molecule CXCR4 antagonists based on the use of computational modelling studies in concert with experimental determination of in vitro activity against CXCL12-induced intracellular calcium mobilisation, proliferation and chemotaxis. Molecular modelling proved to be a useful tool in rationalising our observed potencies, as well as informing the direction of the synthetic efforts aimed at producing more potent compounds.
authors.affiliation: Institute of Cancer Therapeutics, University of Bradford, Bradford, United Kingdom.
authors.forename: Victoria
authors.initials: V
authors.lastname: Vinader
authors.forename: Djevdet S
authors.initials: DS
authors.lastname: Ahmet
authors.forename: Mohaned S
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Patterson
authors.forename: Kamyar
authors.initials: K
authors.lastname: Afarinkia
mesh_terms: D045744:Cell Line, Tumor; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019718:Receptors, CXCR4; D054852:Small Molecule Libraries