HECT E3 ubiquitin liagase inhibitors and uses thereof

Inventors

Kiyokawa, Hiroaki • Mishra, Rama K. • LUAN, Chi-Hao

Assignees

Northwestern University

Abstract

Disclosed herein are compounds, compositions, and methods for inhibiting HECT E3 ubiquitin ligases. In some embodiments, the compounds are formulated as a pharmaceutical composition and administered to a subject in need thereof. In some embodiments, the subject in need thereof is diagnosed with a neurological disease or a cancer characterized by increased or ectopic HECT E3 ligase activity.

Core Innovation

The disclosure relates to inhibiting the activity of a HECT E3 ubiquitin ligase in a subject in need thereof. The problem addressed is the need for therapeutic approaches that target increased or ectopic HECT E3 ubiquitin ligase activity, and the disclosure emphasizes inhibition where the target can include UBE3A/E6AP.

The disclosure describes administering an effective amount of a compound of Formula I, including stereoisomers, pharmaceutically acceptable salts, or combinations. Formula I defines a substituent R selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl optionally substituted with alkyl, and heteroaryl, and the disclosure further defines specific inhibitor structures assigned as Formula II, including Zinc 23375107 and compound #3, and Formula III, compound #3-1.

The disclosure also identifies therapeutic indications for conditions with increased or ectopic HECT E3 ubiquitin ligase activity. These include neurological disorders such as Angelman syndrome and Dup15q/ASD, and cancers associated with HPV and other contexts, and the disclosure supports the approach with described analyses of inhibition and binding and reports cytotoxicity in HPV-positive HeLa cells for compound #3-1.

Claims Coverage

The independent claim covers a method of inhibiting a HECT E3 ubiquitin ligase in a subject by administering a Formula I compound, stereoisomer, pharmaceutically acceptable salt, or combination thereof, with one inventive feature centered on the defined R substituent scope. Dependent claims further specify particular compound formulas, disease or condition context, UBE3A/E6AP, and administration routes.

Overall, the claim set centers on inhibiting a HECT E3 ubiquitin ligase by administering an effective amount of a Formula I compound with a defined R substituent scope, with dependent claims further specifying Formula II or Formula III compound inclusion, linking to diseases or conditions with increased HECT E3 activity, optionally identifying UBE3A/E6AP, and limiting administration routes to oral, parenteral, topical, or local.

Stated Advantages

Documented Applications