Nonpeptidic molecules that block the chemokine receptor, CXCR4, for treatment of proliferative disorders including inhibition of cancer metastasis.
- Modulate CXCR4 receptor activity by interfering with SDF-1 ligand binding.
- Inhibit migration of metastatic cancer cells by blocking chemokine receptor signaling.
- Show increased bioavailability and efficacy over known CXCR4 antagonists.
Most cancer deaths are attributed to metastasis, the migration of cancerous cells from primary tumor origin. Although several strategies have been developed to prevent metastasis, few viable commercial treatments are available. Current therapeutic strategies aimed at regulating adhesion of endothelial cells with antibodies or adhesion molecules have offered mixed results. Given that nearly 14 million new worldwide cancer cases will be diagnosed this year, and nearly 90% of all cancer deaths are due to metastasis, the potential market for a therapy inhibiting metastasis is massive.
CXCR4 is a chemokine receptor, a type of G-protein coupled receptor that plays important cellular roles in cytoskeletal arrangement, migration, inflammation, and differentiation. The chemokine T stromal cell derived factor 1 (SDF-1) binds specifically to CXCR4. High levels of SDF-1 have been correlated to metastatic tumor migrations and vascularization events. Blocking SDF-1 from binding to CXCR4 inhibits these events and reduces metastatic incidence. Most CXCR4 antagonists are peptides with problems in absorption, distribution, metabolism, excretion, or toxicity. To overcome the complications due to these peptides, Emory researchers have developed nonpeptidic compounds capable of inhibiting CXCR4 receptor signaling thereby interfering with pathogenic downstream signaling pathways. This strategy offers novel therapeutic potential for preventing proliferative diseases, specifically metastatic cancer.
Compounds have been studied in cellular and mouse models.