Discovery (Lead Identification)
Topoisomerase enzymes play an important role in cancer progression by controlling changes in DNA structure through catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. Therefore, topoisomerases are important targets for cancer chemotherapy. Many topoisomerase 1 (TOP1) inhibitors such as camptothecin, rinotecan, and topotecan are widely used anti-cancer agents that work by stabilizing the TOP1-DNA cleavage complex. Stabilization causes irreversible double-strand DNA breaks, eventually leading to the death of replicating cancer cells. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme that plays a role in allowing cells to escape from TOP1 inhibitor-induced cell death by catalyzing the clearance of TOP1-DNA complexes. This activity led researchers to consider TDP1 a molecular target for the sensitization of replicating cancer cells to camptothecin and related chemotherapeutic agents.
Scientists at the National Cancer Institute (NCI) discovered recifin, a unique cysteine-rich cyclic peptide that inhibits the human protein tyrosyl-DNA phosphodiesterase 1 (TDP1). The peptide was isolated from a natural source, the sponge Axinella sp. The three-dimensional structure of recifin was determined by NMR and found to represent a completely new structural class unlike previously published cyclic peptides. Recifin inhibits TDP1 via an allosteric mechanism of inhibition and is the first identified allosteric inhibitor of this protein. TDP1 is important for cancer chemotherapy because its inhibition can restore cancer-cell sensitivity to clinically-used topoisomerase inhibitors.
NCI seeks research co-development partners and/or licensees for the development of recifin and its analogues as new chemosensitizing agents in adjunct therapies with topotecan, irinotecan and related chemotherapeutic agents.