Furoquinolinediones as inhibitors of TDP2
Inventors
An, Linkun • Marchand, Christophe • Pommier, Yves
Assignees
US Department of Health and Human Services
Publication Number
US-11999747-B2
Publication Date
2024-06-04
Expiration Date
2036-01-08
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Abstract
Compounds of Formula I and the pharmaceutically acceptable salts thereof are disclosedThe 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 provides compounds of Formula I and their pharmaceutically acceptable salts, described with detailed substituent variables such as X1, X2, and R1-4. These compounds serve as inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2). Pharmaceutical compositions containing these compounds and methods for treating cancers responsive to TDP2 inhibition by administering these compounds are also disclosed.
The problem addressed stems from the essential role of topoisomerases in DNA replication, making them primary targets for cancer therapy. Topoisomerase inhibitors trap cleavage complexes, halting replication and triggering apoptosis, but cells can repair these complexes via tyrosyl-DNA phosphodiesterases (TDPs), particularly TDP2 for Top2-DNA cleavage complexes. Inhibition of TDP2 is therefore a promising strategy to enhance cancer treatment efficacy, potentially as monotherapy or in combination with Top2 inhibitors.
This invention aims to provide effective inhibitors of TDP2 that can prevent repair of trapped topoisomerase-DNA complexes, thereby enhancing anticancer activity. The compounds include a broad chemical scope and formulations, allowing for therapeutic regimens targeting various cancer types. Methods of manufacture, detailed compositions, and treatment modalities using compounds of Formula I are presented to address the limitations of current therapies that do not sufficiently inhibit TDP2-mediated repair.
Claims Coverage
The patent includes a set of 16 claims featuring 1 independent chemical compound claim, a pharmaceutical composition claim, and method of treatment claims. The inventive features are centered on the chemical structure of compounds and their therapeutic use in TDP2 inhibition and cancer treatment.
Compound of Formula I with specified variable substitutions
A compound or pharmaceutically acceptable salt thereof of Formula I characterized by specific substituents: Y2 being nitrogen, R1 as C1-C6alkoxy optionally replaced with —O— or —N(R7)— and substituted with groups like hydroxyl or halogen, and R2 being halogen, C1-C6haloalkyl, cycloalkyl, or substituted phenyl; including variations such as R2 as -J-Q groups, Y1 as oxygen, and other structural features.
Pharmaceutical composition
A pharmaceutical composition comprising a compound or salt of Formula I together with a pharmaceutically acceptable carrier.
Method of treating cancer by inhibiting TDP2
A method of treating cancer by administering a therapeutically effective amount of a compound or salt of Formula I to a patient in need, thereby inhibiting tyrosyl-DNA phosphodiesterase 2.
Combination therapy with Topoisomerase 2 inhibitors
Methods where the TDP2 inhibiting compound is administered in combination with one or more additional compounds, where at least one additional compound is a known topoisomerase 2 inhibitor.
Combination therapy with specific chemotherapeutic agents
Methods of treating cancer by administration of the TDP2 inhibitor along with additional active agents chosen from etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticines, aurintricarboxylic acid, and HU-331.
Targeted cancer types
Treatment methods specifically targeting cancers such as glioma, acute myelogenous leukemia, myelodysplastic/myeloproliferative neoplasms, sarcoma, non-Hodgkin's lymphoma, astrocytoma, melanoma, various lung cancers, cervical, rectal, ovarian, cholangiocarcinomas, chondrosarcoma, and colon cancer.
The claims cover the novel chemical entities of Formula I with defined substitutions, their pharmaceutical formulations, and therapeutic methods for treating cancers via TDP2 inhibition, both as monotherapy and in combination with topoisomerase 2 inhibitors, directed at a variety of cancer types.
Stated Advantages
Inhibitors of TDP2 may potentiate the antiproliferative activities of Top2 inhibitors, enhancing cancer treatment efficacy by preventing repair of topoisomerase-DNA cleavage complexes.
TDP2 inhibitors could serve as sole therapeutic agents or provide synergistic effects when combined with existing topoisomerase inhibitors like etoposide and doxorubicin.
The compounds have broad applicability against various cancers, including both solid tumors and disseminated cancers, potentially improving clinical outcomes.
Documented Applications
Treatment of cancers responsive to TDP2 inhibition.
Treatment of cancers selected from 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.
Pharmaceutical compositions containing compounds of Formula I administered orally, topically, parenterally, by inhalation, sublingually, transdermally, rectally, or ophthalmically.
Use in combination cancer therapies with topoisomerase 2 inhibitors and other chemotherapeutic and biological agents.
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