Furoquinolinediones as inhibitors of TDP2
Inventors
An, Linkun • Marchand, Christophe • Pommier, Yves
Assignees
Sun Yat Sen University • US Department of Health and Human Services
Publication Number
US-10906914-B2
Publication Date
2021-02-02
Expiration Date
2036-01-08
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Compounds of Formula I and the pharmaceutically acceptable salts thereof are disclosed Formula I. The variables X1, X2, and R1-4 are disclosed herein. The compounds are useful for treating cancer and related proliferative diseases. Pharmaceutical compositions containing compounds of Formula I and methods of treatment comprising administering compounds of Formula I are also disclosed.
Core Innovation
The invention discloses compounds of Formula I and their pharmaceutically acceptable salts as inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2). These compounds are characterized by specific chemical substitutions and variations defined within Formula I, with detailed embodiments describing various group substitutions such as alkyl, alkoxy, cycloalkyl, phenyl, and heterocyclic moieties. The compounds are provided along with methods for their manufacture, pharmaceutical compositions containing them, and methods of treatment employing these compounds targeting TDP2 inhibition.
The problem addressed by the invention arises from the role of topoisomerases in DNA replication and their targeting by existing cancer therapies using topoisomerase inhibitors. Tyrosyl-DNA phosphodiesterases, including TDP2, repair trapped topoisomerase-DNA cleavage complexes, which diminishes the efficacy of these therapies. Therefore, inhibiting TDP2 represents a therapeutic strategy to potentiate the effects of topoisomerase inhibitors and provide synergistic treatments for cancer.
The invention provides methods of treating cancer and related proliferative diseases by administering the disclosed compounds or compositions. The compounds inhibit TDP2, thereby interfering with DNA repair mechanisms that enable cancer cell survival in the presence of topoisomerase inhibitors. The disclosed invention spans compounds with defined structural features, compositions, and combination treatment regimens involving TDP2 inhibitors and topoisomerase 2 inhibitors.
Claims Coverage
The patent includes 17 claims focusing on compounds of Formula I and their pharmaceutical applications. There are multiple inventive features related to chemical structure specifics and therapeutic methods.
Compounds of Formula I and their pharmaceutically acceptable salts
The invention claims compounds characterized by the Formula I structure where specific atoms and substituents (e.g., X1, X2, R1-R6) meet defined chemical parameters. These compounds include variations such as —O-A-B substituents with linkers and heterocyclic groups and specific substitutions on phenyl and heteroaryl groups.
Specific structural definitions of R1 and R2 substituents
R1 is defined as —(C0-C6alkyl)cycloalkyl or —O-A-B with B being a phenyl or heteroaryl group substituted with defined chemical groups. R2 is defined to include halogen, C1-C6alkyl, haloalkyl, cycloalkyl, or phenyl with specific substitution patterns. R3 and R4 are hydrogen in certain claims.
Pharmaceutical compositions comprising the compound or salt of Formula I
Pharmaceutical compositions include a compound or salt of Formula I combined with pharmaceutically acceptable carriers, enabling administration for therapeutic use.
Methods of treating cancer by inhibiting TDP2
Methods include administering a therapeutically effective amount of a compound or salt of Formula I to a patient in need, either alone or in combination with additional active agents such as topoisomerase 2 inhibitors.
Combination therapy with topoisomerase 2 inhibitors
The method includes administering the compound in combination with one or more additional compounds where at least one is a known topoisomerase 2 inhibitor, including agents like etoposide and doxorubicin.
Treatment of specific cancer types
The method covers treatment of various cancers responsive to TDP2 inhibition, including glioma, acute myelogenous leukemia, sarcoma, non-Hodgkin's lymphoma, melanoma, non-small cell lung cancer, ovarian cancer, colon cancer, and others specified in the claims.
The claims comprehensively cover the chemical structures of Formula I compounds, their pharmaceutical formulations, and therapeutic methods utilizing these compounds either as monotherapy or in combination with topoisomerase 2 inhibitors for treatment of multiple cancer types via TDP2 inhibition.
Stated Advantages
The compounds serve as effective TDP2 inhibitors useful in treating cancers and proliferative diseases.
Inhibition of TDP2 enhances the antiproliferative activity of topoisomerase 2 inhibitors, providing potential synergy in combination therapies.
Pharmaceutical compositions disclosed allow for effective administration of these inhibitors either alone or combined with known chemotherapeutics.
Documented Applications
Treatment of cancer and related proliferative diseases responsive to TDP2 inhibition.
Use as monotherapy or in combination with topoisomerase 2 inhibitors such as etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, and HU-331.
Treatment of a wide range of cancers including glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic/myeloproliferative neoplasms, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, small cell lung cancer, cervical cancer, rectal cancer, ovarian cancer, cholangiocarcinomas, chondrosarcoma, and colon cancer.
Interested in licensing this patent?