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

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Scientists at National Cancer Institute (NCI) Center for Cancer Research (CCR) identified selective tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors that may be used in combination with topoisomerase 1 (TOP1) inhibitors for synergistic treatment of solid tumors. NCI seeks research co-development partners and/or licensees for commercializing the TDP1 inhibitors as part of an anti-cancer therapy.
NIH Reference Number
Product Type
  • Cancer, TOP1, Topoisomerase 1, TDP1, Tyrosyl-DNA phosphodiesterase 1, Solid Tumor, Zhao, Burke
Collaboration Opportunity
This invention is available for licensing and co-development.
Description of Technology

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.

Potential Commercial Applications
  • Combination therapy with TOP1 inhibitors for cancer treatment
  • Incorporation into Proteolysis Targeting Chimeric or Antibody-Drug Conjugate therapeutics
Competitive Advantages
  • Irreversible inhibition of TDP1
  • Selectivity for TDP1 over TDP2
  • Small molecules capable of accessing and binding to the catalytic machinery to cause cancer cell death
  • Currently, no FDA-approved TDP1 inhibitors
Development Stage

Zhao, X.Z. et al. Small molecule microarray identifies inhibitors of tyrosyl-DNA phosphodiesterase 1 that simultaneously access the catalytic pocket and two substrate binding sites [34163656]

Patent Status
  • U.S. Provisional: U.S. Provisional Patent Application Number 63/141,634, Filed 26 Jan 2021
  • PCT: PCT Application Number US2022/013946, Filed 26 Jan 2022
Therapeutic Area
Sunday, December 4, 2022