Compounds for cancer chemotherapeutic sensitization
Inventors
Wang, Zhengqiang • Kankanala, Jayakanth • Pommier, Yves
Assignees
University of Minnesota System • US Department of Health and Human Services
Publication Number
US-10617706-B2
Publication Date
2020-04-14
Expiration Date
2039-02-04
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Abstract
The invention provides a compound of formula (I), (II) or (III): wherein R1, R2, R3, R4 and R5 have any of the values described in the specification, as well as compositions comprising a compound of formula (I), (II) or (III). The compounds and compositions are useful as chemotherapeutic sensitizing agents.
Core Innovation
The invention provides compounds of formula (I), (II), or (III) that are useful as chemotherapeutic sensitizing agents. These compounds possess specific substituents defined in the specification, and their chemical structures are designed to inhibit tyrosyl-DNA phosphodiesterase II (TDP2). The invention also encompasses compositions comprising these compounds, pharmaceutical formulations, methods for sensitizing cancer cells toward therapy, and methods for treating cancer in animals using these compounds in combination with chemotherapeutic agents, particularly Topoisomerase II (Top2) poisons.
The problem being solved arises from the role of TDP2 as a DNA repair enzyme that specifically repairs Top2-mediated DNA damages, including abortive Top2 cleavage complexes trapped by Top2 poisons. The normal function of TDP2 leads to resistance of cancer cells to Top2 poisons, which are major drugs for treating various cancers. Current TDP2 inhibitors are underexplored, poorly understood, and have weak cellular efficacy. Thus, improved TDP2 inhibitors are needed that effectively sensitize cancer cells to allow use of Top2 poisons at lower and safer doses.
Claims Coverage
The patent contains three independent claims directed to compounds of formula (I), (II), and (III), respectively, covering chemical compositions and pharmaceutical uses.
Compounds of formula (I), (II), or (III) with defined substituents
The invention claims compounds of formula (I), (II), or (III) wherein substituents R1, R2, R3, R4, and R5 are defined with specific groups such as phenyl, benzyl, alkyl optionally substituted with halo or functional groups including carboxy, alkoxycarbonyl, phosphates, boron groups, sulfonyl fluorides, and others. The precise chemical structures and substitution patterns are detailed in the patent.
Pharmaceutical compositions comprising compounds and excipients
Compositions comprising a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof together with pharmaceutically acceptable excipients are claimed, facilitating administration and therapeutic use.
Pharmaceutical compositions combining compounds with chemotherapeutic agents
Pharmaceutical compositions comprising (1) a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, (2) a chemotherapeutic agent such as a Top2 poison, and (3) pharmaceutically acceptable excipients are claimed for combinational cancer therapy.
Methods of sensitizing cancer cells and treating cancer
Methods involving contacting cancer cells with the compounds to sensitize them toward therapy, and methods of treating cancer in animals by administering the compounds in combination with chemotherapeutic agents, especially Top2 poisons, are claimed.
Overall, the claims cover novel compounds with defined chemical structures, their pharmaceutical formulations, combinational usage with chemotherapeutic agents, and methods for sensitizing and treating cancer, establishing a comprehensive protection of the inventive sensitization approach.
Stated Advantages
The compounds of the invention are effective to sensitize cancer cells to Top2 poisons, thereby potentially allowing the use of lower and safer doses of chemotherapeutic agents.
The compounds demonstrate improved efficacy in cancer cell lines compared to previously reported TDP2 inhibitors, achieving greater maximal efficacy at lower concentrations.
Modifications to the compounds, such as attaching electrophilic warheads for serine trapping, are tolerated and may provide dual mechanism TDP2 inhibition, enhancing therapeutic potential.
Documented Applications
Use of the compounds as chemotherapeutic sensitizing agents in cancer treatment by combining with Top2 poisons such as etoposide, teniposide, doxorubicin, or daunorubicin.
Pharmaceutical compositions comprising the compounds for therapeutic or prophylactic treatment of cancer in animals, particularly mammals such as humans.
Methods of sensitizing cancer cells to therapy in vitro and methods of treating cancer in animals by administration of the compounds together with chemotherapeutic agents.
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