Thioxothiazolidinone Derivatives — A Novel Class of Anti Cancer Agents

The invention provides for a novel class of heterocyclic compounds (i.e. thioxothiazolidinone derivatives) that exhibit anticancer activity in a unique mechanism. More specifically, the compounds of the invention act as inhibitors of the enzyme human tyrosyl DNA phosphodiesterase1 (Tdp1), a DNA repair enzyme involved in topoisomerase1 (Top1) mediated DNA damage, such as damage induced by the Top1 inhibitors and chemotherapeutic agents, camptothecins. As such, these compounds can serve as potentiators of camptothecins. The experimental data indeed point at a synergistic effect achieved in a combination therapy of the thioxothiazolidinone derivatives of the invention and the established anticancer agents camptothecins. Moreover, due to this synergistic effect, a lower therapeutic dose of the latter may be needed, resulting in reduced side effects. In addition, it is possible that the Tdp1 inhibitors of the invention may be effective as anti tumor agents on their own. This is based on the fact that Tdp1 is involved also in repairing DNA damage resulting from oxygen radicals, and the observation that tumors contain excess free radicals.

Potential Commercial Applications: Competitive Advantages:
  • Effective cancer therapy in combination with camptothecins
  • Cancer therapy as standalone anti cancer agents
  The compounds of the invention act in unique mechanism that can enhance the therapeutic efficacy of the anticancer drugs camptothecins, and at the same time can serve as standalone anticancer agents.

Yves Pommier (NCI)

Intellectual Property:
PCT Application No. PCT/US1259515
US Application No. 61/545,308

Marchand C, et al. PMID 19139134
Dexheimer TS, et al. PMID 18473723
Dexheimer TS, et al. PMID 19883083

Licensing Contact:
Uri Reichman , Ph.D., M.B.A.
NIH Office of Technology Transfer
Phone: 301-435-4616

OTT Reference No: E-239-2011/0

Updated: Jan-17-2012