Discovery and computer aided potency optimization of a novel class of small molecule CXCR4 antagonists

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.