Cemadotin Hydrochloride

Antibody–drug conjugates are increasingly being used for cancer therapy, but little is known about their ability to promote anticancer immunity, which may lead to long-lasting remissions. We investigated the therapeutic effect of antibody-based pharmacodelivery of cemadotin, a cytotoxic drug, and IL2, a strong proinflammatory cytokine. Using the F8 antibody, which selectively localizes to the tumor neovasculature, combination treatment led to tumor eradication, in a process dependent on CD8+ T cells and natural killer cells in the C1498 syngeneic mouse model of acute myelogenous leukemia. The clinical combination of antibody–drug conjugates and antibody–cytokine proteins should be facilitated by their orthogonal toxicity profiles. Mol Cancer Ther; 13(7); 1772–6. ©2014 AACR.

Chemotherapeutic resistance due to over expression of Inhibitor of Apoptosis Proteins (IAPs) XIAP, survivin and livin has been observed in various cancers. In the current study, Molecular Dynamics (MD) simulations were carried out for all three IAPs and a common ligand binding scaffold was identified. Further, a novel sequence based motif specific to these IAPs was designed. SMAC is an endogenous inhibitor of IAPs. Screening of ChemBank for compounds similar to lead SMAC-non-peptidomimetics yielded a cemadotin related compound NCIMech_000654. Cemadotin is a derivative of natural anti-tumor peptide dolastatin-15; hence these compounds were docked against all three IAPs. Based on our analysis, we propose that NCIMech_000654/dolastatin-15/cemadotin derivatives may be investigated for their potential in inhibiting XIAP, survivin and livin.