Novel peptide mimetic small molecules of the HAV motif in N-cadherin inhibit N-cadherin-mediated neurite outgrowth and cell adhesion

The cell adhesion molecule, N-cadherin, stabilizes cell-cell junctions and promotes cellular migration during tissue morphogenesis in development. N-cadherin is also implicated in mediating tumor progression and metastasis in cancer. Therefore, developing antagonists of N-cadherin adhesion may be of therapeutic value in cancer treatment. The amino acid sequence HAV in the extracellular domain of N-cadherin is required for N-cadherin-mediated adhesion and migration. A cyclic peptide, ADH-1, derived from the N-cadherin HAV site is an effective antagonist of N-cadherin-mediated processes and is now in clinical trials for cancer chemotherapy. Because it is a peptide, ADH-1 has certain limitations as a drug, namely its metabolic instability and lack of oral delivery. Adherex set out to identify small molecule antagonists of N-cadherin, which would be more amenable to therapeutic use. Using three-dimensional computational screening, Adherex identified a set of small molecules as potential antagonists with sufficient structural similarity to the HAV region of N-cadherin. We tested the ability of these small molecules to interfere with two N-cadherin-dependent processes: neurite outgrowth (axonal migration) and N-cadherin-dependent cell adhesion. We identified 21 N-cadherin antagonists of varying potency. More importantly, our studies demonstrate that these compounds are significantly more potent than ADH-1 at perturbing N-cadherin-mediated processes. The IC(50) of ADH-1 is 2.33 mM while the IC(50) of the small molecules ranges from 4.5 to 30 microM. Given the efficacy of ADH-1 for treating cancer, these small molecule antagonists will be highly effective in treatment of cancer metastasis and conditions of aberrant neurite outgrowth, such as neuropathic pain.