Azaindenoisoquinoline compounds and uses thereof
Inventors
Cushman, Mark S. • Wang, Ping • Pommier, Yves George • Elsayed, Mohamed S. A.
Assignees
Purdue Research Foundation • US Department of Health and Human Services
Publication Number
US-10875860-B2
Publication Date
2020-12-29
Expiration Date
2037-12-19
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Tyrosyl-DNA Phosphodiesterases 1 and 2 (Tdp1 and Tdp2) can repair damaged DNA resulting from topoisomerase inhibitors (e.g. Top1) and a variety of other DNA-damaging agents. 7-Azaindenoisoquinolines that are inhibitors of each of Top1, Tdp1 and Tdp2 are disclosed. Also described are methods for preparing azaindenoisoquinoline and methods for treating patients of a cancer using the disclosed azaindenoisoquinoline compounds or a pharmaceutical formulation thereof.
Core Innovation
The present disclosure relates to novel azaindenoisoquinoline compounds that function as triple inhibitors of Topoisomerase 1 (Top1) and Tyrosyl-DNA Phosphodiesterases 1 and 2 (Tdp1 and Tdp2). These compounds are described as useful for the treatment of cancer, with pharmaceutical compositions and methods for administering these compounds to cancer patients also disclosed.
The problem addressed is that existing cancer therapies targeting Top1 are limited by the DNA repair mechanisms mediated by Tdp1 and Tdp2, which contribute to drug resistance. While Top1 inhibitors like camptothecins and indenoisoquinolines are effective by stabilizing DNA-Top1 cleavage complexes leading to tumor cell death, resistance arises since Tdp1 and Tdp2 can repair the Top1-mediated DNA damage. This necessitates the development of compounds that inhibit Top1 along with Tdp1 and Tdp2 to overcome resistance and improve therapeutic effects.
The invention discloses azaindenoisoquinoline compounds having specific chemical structures with various substituents that act simultaneously as inhibitors of Top1, Tdp1, and Tdp2. These compounds show potent Top1 inhibitory activity, as well as measurable inhibition against Tdp1 and Tdp2, and demonstrate cytotoxic effects against a range of human cancer cell lines. The disclosure includes detailed synthetic routes, characterization, and biological assay data supporting their utility as triple inhibitors for cancer treatment.
Claims Coverage
The patent contains one independent compound claim and related claims for compositions and therapeutic methods, encompassing five inventive features focused on the compound structures and their applications.
Compound of formula (II) with specified substituents
Discloses a compound of formula (II) featuring substituent R1 as 3-fluoro or 3-chloro, and R2 selected from methylamine, ethylamine, or isopropylamine groups, forming a chemical structure with defined inhibitory activity.
Pharmaceutical composition comprising the compound
Describes a pharmaceutical composition comprising the compound of formula (II) or its pharmaceutically acceptable salt together with one or more pharmaceutically acceptable carriers, diluents, and excipients suitable for therapeutic use.
Method for treating cancer by administering pharmaceutical composition
Covers a method for treating patients having cancers selected from lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancer by administering a therapeutically effective amount of the pharmaceutical composition disclosed.
Method for treating cancer by administering the compound
Concerns a method for treating the same set of cancers by administering a therapeutically effective amount of the compound or its salt along with pharmaceutically acceptable carriers and excipients.
Method for treating cancer using the compound in combination with other therapeutics
Describes a method of cancer treatment involving administration of the compound or salt together with one or more other compounds with the same or different modes of action, alongside pharmaceutically acceptable carriers, diluents, and excipients.
These claims focus on the novel chemical entities of azaindenoisoquinolines with particular substituents, their pharmaceutical compositions, and methods of treating various cancers using these compounds alone or in combination with other treatments, emphasizing the triple inhibition of Top1, Tdp1, and Tdp2.
Stated Advantages
The compounds act as triple inhibitors of Top1, Tdp1, and Tdp2, potentially overcoming drug resistance mechanisms in cancer therapy.
They exhibit potent anticancer activity with significant cytotoxicity against diverse human cancer cell lines.
The compounds can be used alone or in combination with other anticancer agents or therapeutic modalities, allowing flexibility in cancer treatment regimens.
Improved synthetic methods provide higher yields facilitating structure-activity relationship studies and practical preparation on a gram scale.
Documented Applications
Treatment of various cancers, including lung cancer, colon cancer, central nervous system (CNS) cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer using the disclosed azaindenoisoquinoline compounds or pharmaceutical compositions thereof.
Interested in licensing this patent?