CXCR4 chemokine receptor antagonists : new metallodrugs

Khan, Abid

Abstract

Chemokine receptors are a target of growing interest for new therapeutic drugs, as their role in multiple disease states has been demonstrated. The CXCR4/ CXCL12 pairing has been implicated in HIV and cancer, as well as chronic inflammatory diseases, including asthma and rheumatoid arthritis. HIV uses CXCR4 or CCR5 receptors in the key binding step of the infection process, leading to the idea that drugs could be developed to block this interaction. Cancer metastasis has also been linked to cellular communication via the chemokine pathways and hence, receptor antagonists could potentially inhibit this important pathway of disease progression. Small synthetic CXCR4 antagonists exist including AMD3100 (Mozobil®/Plerixafor), which has been identified as a potent CXCR4 antagonist exhibiting anti-HIV, anti-inflammatory and anti-tumour activity. Configurationally restricted analogues of AMD3100 complexed to metal ions have improved binding characteristics compared to AMD3100 and its metal complexes.

Herein we report the binding of a new class of cyclen, cyclam and tris-cyclam based complexes in vitro. Compounds competed effectively in anti-CXCR4 competition assays with the tricyclam linear complex displaying improved binding characteristics. The difference in activity of the compounds is discussed in relation to the different possible binding interactions that are occurring. Furthermore, a monocyclam derivative conjugated to biotin competed effectively in competition with a CXCR4 mAb, however could not directly be detected via a fluorescent conjugated streptavidin molecule.

Our most potent compound to date, copper(II) cross-bridged bicyclam was found to have a significant higher relative residence time in CXCR4 compared to AMD3100 and copper(II) AMD3100 in vitro. Moreover, copper(II) cross-bridged bicyclam was able to totally block CXCL12 induced and partially block serum induced, invasion of CXCR4 positive cancer cells with a higher potency than AMD3100 and copper(II) AMD3100. This shows the potential of using such a drug in the clinic.

Using CXCR4 mutants, it has been shown that CXCR4 defective degradation and recycling increases invasion in breast cancer cells. Moreover the development of a multicellular tumour spheroid (MTS) is reported that could be used as a preclinical model in the evaluation of the anti-cancer activity of CXCR4 antagonists.

Citation

Khan, A. CXCR4 chemokine receptor antagonists : new metallodrugs. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4216132

• Thesis Type: Thesis
• Deposit Date: Jan 5, 2015
• Publicly Available Date: Feb 23, 2023
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4216132
• Additional Information: Department of Chemistry, The University of Hull
• Award Date: Dec 1, 2009