The C-X-C chemokine receptor-4 (CXCR4) is a seven-transmembrane G-protein coupled receptor (GPCR). It is a member of the family I GPCR or rhodopsin-like GPCR family. The chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) is a CXC chemokine peptide. Meanwhile, it is the natural ligand for CXCR4. Importantly, the CXCR4 is not only on a wide variety of leukocytes but also on cells outside the immune system. CXCR4 is far more than a coreceptor for HIV, playing an important role in cancer metastasis, regulation of stem cell trafficking, and neovascularization. CXCR4 is crucial for the homing of tumor cells to the bone marrow microenvironment and drug resistance. Consequently, CXCR4 antagonists have potential as chemo-sensitizers in leukemia treatment. WZ811 is an orally active, highly potent competitive antagonist of CXCR4.

WZ811 efficiently inhibits CXCR4/SDF-1 (or CXCL12)-mediated modulation of cAMP levels (EC₅₀=1.2 nM) and SDF-1 induced Matrigel invasion in cells (EC₅₀=5.2 nM). In addition, it inhibits TF-1 and UT-7 cell proliferation in a dose-responsive manner for 24 h and 48 h. WZ811 also inhibits CLL cell motility and colony formation ability. Docetaxel results in more effective inhibition of proliferation in TF-1 (IC50=8.95 nM) and UT-7 (IC50=6.53 nM) cell treated with WZ811. Therefore, it suggests that WZ811 induces cell apoptosis and increases the sensitivity of cells to docetaxel. In addition, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) significantly decreased as well as Caspase-3 occurred after WZ811 treatment.

In vivo, WZ811 inhibits chronic lymphocytic leukemia growth. Data shows it can suppress the in vivo tumor growth through inhibiting CXCR4/PI3K/AKT/mTOR signaling.

In summary, WZ811 is the highly potent competitive antagonist of CXCR4. It significantly inhibits chronic lymphocytic leukemia progression and tumorigenesis in vitro and in vivo.