3-(hydroxy)-pyridin-4(1H)-one compounds and methods of making and using the same
Inventors
Oyelere, Adegboyega K. • KHODAVERDIAN, Verjine • Tapadar, Subhasish
Assignees
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Publication Number
US-12521382-B2
Publication Date
2026-01-13
Expiration Date
Abstract
Compositions and methods for inhibiting histone lysine demethylases are provided. Several new DFP-based KDM inhibitors which alter the velocity of HP1-mediated heterochromatin gene repression are provided.
Core Innovation
The disclosure provides substituted and bis(3-hydroxy-2-methylpyridin-4-one) derivatives derived from deferiprone, including BisDFP compounds and triazole-linked analogues according to Formula I, alongside hydrates, solvates, pharmaceutically acceptable salts, and resolved single isomers thereof. In Formula I, variable C is substituted or unsubstituted alkyl or substituted or unsubstituted aryl. These compounds function as histone lysine demethylase inhibitors, demonstrating concentration-dependent KDM6A inhibition and tumor-cell antiproliferative activity.
The derivatives exhibit tumor-selective antiproliferative activity with preferential potency against triple-negative MDA-MB-231 breast cancer cells relative to deferiprone. Tested compounds such as 1d and 2u increase cellular H3K4me3 and H3K27me3 levels, while compounds 2v, 2w, and 3g inhibit HP1-stimulated heterochromatin formation. Documented therapeutic treatment applications encompass breast cancer, prostate cancer, and other cancers, though the precise problem being solved is not explicitly described in the provided patent text.
Claims Coverage
The supplied claims identify one independent claim directed to compounds of Formula I, with three principal inventive features covered across the independent and dependent claims.
Formula I compounds and forms thereof
Independent claim 1 covers a compound according to Formula I, wherein C is substituted or unsubstituted alkyl or substituted or unsubstituted aryl, or a hydrate, solvate, pharmaceutically acceptable salt, or resolved single isomer thereof, wherein the supplied claim text does not render structures for substituents A and B.
Pharmaceutical compositions
A dependent claim covers a pharmaceutical composition comprising the compound of claim 1.
Methods involving enzyme inhibition and cancer treatment
Dependent claims cover administering the compound to inhibit histone lysine demethylase activity and methods directed to reducing tumor growth, tumor burden, or cancer-cell proliferation, specifically identifying breast cancer and prostate cancer, with a further dependent claim covering co-administration of a chemotherapeutic agent.
The claims center on the Formula I compound genus and its specified hydrate, solvate, pharmaceutically acceptable salt, and resolved single isomer forms, with dependent claim coverage extending to pharmaceutical compositions and methods of histone lysine demethylase inhibition and cancer treatment.
Stated Advantages
The described compounds exhibit inhibitory activity against selected histone lysine demethylases, including concentration-dependent KDM6A inhibition reaching 96 to 100% at 10 micromolar.
Reported derivatives show tumor-selective antiproliferative activity with preferential activity against triple-negative MDA-MB-231 breast cancer cells, demonstrating potency enhanced up to 65-fold or 93-fold relative to deferiprone to reduce tumor burden and cancer-cell proliferation.
Compounds 1d and 2u increase cellular H3K4me3 and H3K27me3 at lower concentrations than deferiprone.
Compounds 2v, 2w, and 3g inhibit HP1-stimulated heterochromatin formation.
Documented Applications
Administering a claimed compound to inhibit histone lysine demethylase activity in a subject.
Treating cancer by reducing tumor growth, tumor burden, or cancer-cell proliferation.
Treatment of breast cancer or prostate cancer.
Cancer treatment comprising co-administration of a chemotherapeutic agent in addition to the claimed compound.
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