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

作者：Vinader Victoria; Ahmet Djevdet S; Ahmed Mohaned S; Patterson Laurence H; Afarinkia Kamyar^*

来源：PLos One, 2013, 8(10): e78744.

DOI：10.1371/journal.pone.0078744

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.

• 出版日期2013-10-18