Abstract B50: Design, synthesis, and functional characterization of new cycle-peptides inhibitors for C-X-C chemokine receptor-4

Inhibition of the axis CXCR4/CXCL12 can affect tumor growth and metastases. Moreover, CXCR4 inhibition increases hematopoietic stem cell mobility in patients undergoing autologous transplantation for myeloma and non-Hodgkin lymphoma. Although several inhibitors were described neither one reached satisfactory efficacy, bioavailability and acceptable toxicity. To develop new CXCR4 inhibitors through a rationale design approach, comparative studies were undertaken evaluating the N-terminal structure of the ligand CXCL12 and v-MIP II, an inhibitory chemokine like produced by the herpes virus 8-Kaposi associated. A common amino acidic motif (RFF) was identified in both structures although in inverted orientation. Having as a core this small domain, a new library (20 units) of cycle-peptide molecules was generated. 20 units of cycle-peptide molecules were synthesized that consists of 5 and 7 amino-acid residues cycled by a S-S bridge designed to interact with the receptor CXCR4. The peptides were characterized for functionally CXCR4 interaction through: 1. inhibition of CXCR4 binding; 2. inhibition of migration CXCL12-induced; 3. inhibition of calcium CXCL12-induced; 4. Inhibition of P-Erk CXCL12-induced. Four peptides were identified as possible CXCR4 inhibitors. These four CXCR4 inhibitory peptides were further evaluated for the in vivo efficacy through inhibition of metastasis formation. B16 mouse melanoma cells transfected with CXCR4 were injected in the vein tail in C57 Bl mice and peptide treatment followed for 10 days. Dramatic reduction in number and size of lung metastases were registered in mice peptides-treated. Moreover, xenograft of human renal cancer cells SN12C-EGFP were subcutaneously injected and systemic peptides treatment followed for 10 days. Statistically significant decrease in tumor growth was showed in peptides treated mice. Taken together the data define three new CXCR4 inhibitory peptides, designed through innovative strategy, effective in “in vivo” deserving further development. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B50