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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.

SUBMITTER: Vinader V

PROVIDER: S-EPMC3800133 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Vinader Victoria V Ahmet Djevdet S DS Ahmed Mohaned S MS Patterson Laurence H LH Afarinkia Kamyar K

PloS one 20131018 10

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 o ...[more]

PMID: 24205302

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