Topoisomerase 1B (TOP1) is an enzyme that relieves the torsional strain in DNA. To relieve the torsional strain, TOP1B cleaves one strand of DNA and forms a transient complex called a TOP1-DNA covalent cleavage complex (TOP1cc). TOP1 inhibitors – such as camptothecin – stabilize the TOP1cc and prevent relegation of the broken DNA which, when encountered by replication and transcription machinery, triggers cell death. The DNA damage generated by the TOP1cc can be repaired by several pathways, including tyrosyl-DNA phosphodiesterase 1 (TDP1) pathway.
Inhibitors of TOP1, including camptothecin (CPT), have long been recognized as anti-cancer agents; however, CPT has several known limitations like toxic side effects, chemical instability, poor solubility, and the propensity to drive drug resistance via drug efflux mechanisms. Relevantly, the activity of CPT is in direct competition with TDP1 activity which it must overcome to elicit TOP1-mediated DNA damage and cell death. Thus, much attention has been given to the discovery of non-CPT compounds that target TOP1 for treating tumors.
To this end, investigators at the National Cancer Institute (NCI) and a collaborating institution have discovered and evaluated several oxynitidine derivatives for use as non-CPT inhibitors of TOP1 and/or TDP1. These derivatives can inhibit TOP1 at nanomolar concentrations, eliciting DNA damage and cell death in cancer cell lines. Furthermore, synergistic effects with CPT were also observed with some of the derivatives. In vivo mouse studies showed that the derivatives were generally safe and fairly well tolerated. The weight of tumors were reduced in a dose-dependent manner in mice xenografted with either human colon or breast cancer cells. Finally, the TOP1 inhibitor derivatives exhibited a greatly reduced propensity for drug efflux mediated resistance.
Altogether, the investigators have discovered an array of new compounds targeting the diverse cancers sensitive to TOP1 and TDP1 inhibition. These oxynitidine derivatives are potentially physiologically more tolerable and may lead to better outcomes than CPT. The NCI seeks research co-development and/or potential licensees for oxynitidine derivatives as new topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors for treating cancer.
- TOP1 and TDP1 inhibitors for treating various cancers
- Combinatorial drug treatment options to boost anti-tumor potency
- Novel chemotype for TOP1 and TDP1 inhibitors
- Can potentially be used synergistically with existing therapeutics such as CPT
- These compounds may overcome the limitations of CPT, especially chemical instability and diarrhea
- Commercial development of several derivatives have reached clinical trials
- Limited number of chemotypes reported as TDP1 inhibitors provides good commercial potential given finite competition
Yves G. Pommier M.D., Ph.D. (NCI-CCR), Evgeny A. Kiselev Ph.D. (NCI-CCR), Lin-Kun An Ph.D., Xiao-Ru Zhang, Hao-Wen Wang, Azhar A. Ravji (NCI-CCR), Keli K. Agama Ph.D. (NCI-CCR)
Zhang X-R, et al. Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents. [PMID: 30336023]
- Foreign Filed: - Patent Application 201810827467.1 , Filed 25 Jul 2018
- U.S. Provisional: U.S. Provisional Patent Application Number 62/732,885, Filed 18 Sep 2018
- PCT: PCT Application Number PCT/US2019/043357 , Filed 25 Jul 2019