Compounds 11-13.

<p>Compounds 11-13.</p

A view of the residues surrounding the binding pocket of CXCR4.

<p>A view of the residues surrounding the binding pocket of CXCR4.</p

Structures of TN14003, AMD3100, AMD3465, AMD11070, and GSK812397.

<p>Structures of TN14003, AMD3100, AMD3465, AMD11070, and GSK812397.</p

Preparation of compounds 20 and 21.

<p>Preparation of compounds 20 and 21.</p

Preparation of compounds 6-10.

<p>Preparation of compounds 6-10.</p

Effect of antagonists on CXCL12 induced migration of U87 cells in a two chamber assay.

<p>Effect of antagonists on CXCL12 induced migration of U87 cells in a two chamber assay.</p

Effect of antagonists on CXCL12 induced proliferation of U87 cells

<p>(a) Increase in U87 cell proliferation rate in response to CXCL12. (b) Reduction of CXCL12 induced proliferation of U87 cells by antagonists after 3 days. </p

Discovery and Computer Aided Potency Optimization of a Novel Class of Small Molecule CXCR4 Antagonists

<div><p>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 <i>in vitro</i> 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.</p> </div

Preparation of compound 25.

<p>Preparation of compound 25.</p

Images of U87 cells at the interface of an agarose spot and their subsequent migration into the agarose.

<p>The edge of the agarose spot is highlighted by the dotted white line. The extent of migration is dependent on the presence of CXCL12 ligand whereas cell migration is reduced in the presence of CXCR4 inhibitors (bar = 0.1 mm): (a) control (no CXCL12); (b) 125 nM CXCL12; (c) 125 nM CXCL12 and 200 µM AMD3100; (d) 125 nM CXCL12 and 200 µM ICT5040. (e) Reduction in the migration of cells by ICT5040, AMD3100 and CXCR4 mAb. See methods for experimental details.</p