Phosphodiesterase as a target for cancer therapeutics


Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3'-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its derivatives used clinically. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme involved in the repair of DNA lesions created when the activity of the Topoisomerase 1 (Top1) is inhibited. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin. By reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors.
 



Potential Commercial Applications: Competitive Advantages:

Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its derivatives used clinically.

 

Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways.



Development Stage:
Discovery (Lead Identification)

Inventors:

Yves Pommier (NCI)  ➽ more inventions...

Christophe Marchand (NCI)  ➽ more inventions...


Intellectual Property:

Publications:
Dexheimer TS, et al. 4-Pregnen-21-ol-3,20-dione-21-(4-bromobenzenesulfonate) and related novel steroid derivatives as tyrosyl-DNA phosphodiesterase (Tdp1) inhibitors. PMID 19883083
Marchand C, et al. Identification of phosphotyrosine mimetic inhibitors of human tyrosyl-DNA phosphodiesterase I by a novel AlphaScreen high-throughput assay. PMID 19139134

Collaboration Opportunity:

Licensing and research collaboration


Licensing Contact:
John Hewes, Ph.D.
Email: John.Hewes@nih.gov
Phone: 240-276-5515

OTT Reference No: E-199-2010
Updated: Sep 6, 2016