Novel Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (TDP1) for Treatment of Solid Tumors

Topoisomerase 1 (TOP1) is an essential enzyme that plays a critical role in DNA transcription and replication. TOP1 inhibitors are a known class of anti-cancer agents that work to interrupt DNA replication in cancer cells, causing cell death. Since the discovery of the TOP1 inhibitor camptothecin (CPT) from plant extracts more than 60 years ago, two CPT analogs (irinotecan and topotecan) were approved by the FDA for cancer treatment. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme involved in DNA repair created when TOP1 is inhibited. As a result, targeting TDP1 is considered a potential therapeutic approach to enhance and possibly synergize the potency of TOP1 inhibitors. While TOP1 inhibitors are widely used to treat solid tumors – such as colon, lung, ovarian and certain pediatric cancers – there are currently no drugs targeting TDP1. Many TDP1 inhibitors may potentially have mechanisms of action that are promiscuous and non-specific. Researchers at the NCI developed a series of novel compounds selectively targeting the catalytic domain of TDP1. These small molecules show low micromolar potency against TDP1. X-ray structures of TDP1 bound to some of the small molecules elucidated their catalytic binding modes. The compounds developed at the NCI show selectivity for TDP1 over TDP2.

The NCI seeks proposals from parties interested in licensing and/or co-development for commercializing the use of TDP1 inhibitors as part of a potent and selective anti-cancer combination therapy.