Accurately Assess Drug Residence Time And Anti-Metastatic Effects Of CXCR4 Inhibitors

Metastasis, the spread of cancer cells from the original tumor to secondary locations within the body, is linked to approximately 90% of cancer deaths (Saxe, 2013). The expression of chemokine receptors, such as CXCR4 and CCR7, is tightly correlated with the metastatic properties of breast cancer cells. In vivo, neutralizing the interaction of CXCR4 and its known ligand, SDF1-α (CXCL12), significantly impaired the metastasis of breast cancer cells and cell migration (Muller et al., 2001). Traditionally, the discovery of novel agents has been guided by the affinity of the ligand for the receptor under equilibrium conditions, largely ignoring the kinetic aspects of the ligand-receptor interaction. However, awareness of the importance of binding kinetics has started to increase due to accumulating evidence (Swinney, 2004; Copeland et al., 2006; Tummino and Copeland, 2008; Zhang and Monsma, 2009) suggesting that the in vivo effectiveness of ligands may be attributed to the time a particular ligand resides at its receptor (Drug-Target Residence Time).