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

V. Vinader | Zendy; Djevdet S. Ahmet | Zendy; Mohaned Ahmed | Zendy; Laurence H. Patterson | Zendy; K. Afarinkia | Zendy

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

Author(s) -

V. Vinader,

Djevdet S. Ahmet,

Mohaned Ahmed,

Laurence H. Patterson,

K. Afarinkia

Publication year - 2013

Publication title -

plos one

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 0.99

H-Index - 332

ISSN - 1932-6203

DOI - 10.1371/journal.pone.0078744

Subject(s) - cxcr4 , chemokine , chemokine receptor , chemotaxis , biology , cancer research , computational biology , in vitro , cxcl14 , lung cancer , small molecule , receptor , bioinformatics , immunology , pharmacology , microbiology and biotechnology , medicine , biochemistry

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.

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