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Novel small molecules for chemotherapy sensitization

Technology #20180203
Novel phenoxyphenyldeazaflavin compounds that sensitize cancer cells to widely used topoisomerase inhibitors.

Applications

  • Combination chemotherapy: coadministration with widely-used Top2 poisons (e.g. etoposide, teniposide, doxorubicin or daunorubicin) to sensitize cancer cells.
  • Basic cancer research

Key Benefits & Differentiators

  • Works with existing cancer treatments: Phenoxyphenyldeazaflavin compounds sensitize cancers cto widely used Top2 chemotherapeutics that have been in the clinic more than 50 years.
  • Accesses cells while minimizing toxicity: In cell assays illustrate favorable cytotoxicity and cell permeability profiles.
  • Applicable to many cancers: Works with Top2 inhibitors that are currently used to treat a wide variety of solid tumors and hematologic malignancies.

TDP2 inhibition sensitizes cancer cells toward anticancer therapies

Topoisomerase II (topo II or Top2) poisons, are a major class of drugs widely used to treat cancers including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma and ovarian cancer. These drugs work by generating DNA damage. However, drug resistance can limit the efficacy of treatment. Human tyrosyl-DNA phosphodiesterase II (TDP2) counteracts the effect of Top2 poisons thus repairing the damaged DNA and leading to chemotherapeutic resistance. To mitigate this form of cancer drug-resistance, Dr .Zhengqiang Wang (University of Minnesota) and Dr. Yves Pommier (National Cancer Institute) developed novel  phenoxyphenyldeazaflavin compounds that effectively inhibit TDP2 in cancer cell lines. Through the inhibition of DNA damage repair machinery, these compounds functionally sensitize cancer cells toward widely-used anticancer Top2 poisons.

Demonstrated efficacy in cancer cell lines

While previous deazaflavin compounds inhibit TDP2 in biochemical assays, they have not shown strong efficacy in cancer cells. This new technology, which modifies the critical structural of the deazaflavin core, generates the first-ever compounds that demonstrate strong efficacy in cancer cell lines. Using these new compounds in conjunction with topoisomerase II inhibitors (topo II or Top2) cancer therapies inhibits TDP2, keeping topo II inhibitors effective and preventing resistance.

Phase of Development

  • In Vitro Assessment: Compounds’ anticancer activity demonstrated in biochemical and cell models. Assays carried out show favorable cell permeability and cytotoxicity.
  • Desired Partnerships

    This technology is now available for:

    • License
    • Sponsored research
    • Co-development
    Please contact Kenneth Karanja to share your business’ needs and learn more.

    Publications