Compounds and pharmaceutical composition associated with ubiquitination-proteasome system
Inventors
Yen, Yun • Liou, Jing-Ping • Pan, Shiow-Lin
Assignees
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Publication Number
US-11084786-B2
Publication Date
2021-08-10
Expiration Date
Abstract
The invention relates to new compounds with low cytotoxicity for blocking ubiquitination-proteasome system in diseases. Accordingly, these compounds can be used in treatment of treating disorders including, but not limited to, cancers, neurodegenerative diseases, inflammatory disorders and autoimmune disorders and metabolic disorders.
Core Innovation
The invention relates to low-cytotoxicity compounds that inhibit or target the ubiquitination-proteasome system. The compounds are defined by chemical structures including Formula (I) and Formula (II), with variable substituents R1-R7 and linker X/Y, and the description includes representative embodiments together with tautomers, stereoisomers, solvates, prodrugs, and pharmaceutically acceptable salts.
A stated biological focus is inhibition of ITCH E3 ligase and modulation of ITCH self-ubiquitination, described as ITCH self-ubiquitination (Lys-dependent). The disclosed compounds demonstrate inhibition of ITCH self-ubiquitination and effects related to Lys-dependent polyubiquitylation, and block ITCH self-ubiquitination more efficiently than a control compound.
The invention additionally provides pharmaceutical compositions comprising the low-cytotoxicity compounds and a pharmaceutically acceptable carrier, and therapeutic treatment to a subject by contacting a cell and/or administering an effective amount of the compound or the pharmaceutical composition. Therapeutic indications explicitly include cancer treatment, autoimmune disorders, and treatment to a neoplastic disease, an inflammatory disorder, a neurodegenerative disease or a metabolic disorder.
Claims Coverage
The independent claims provide one therapeutic-treatment method framework covering multiple disease categories, grounded on defined compound structures and their pharmaceutically acceptable forms. The combined claim set identifies six inventive features and further narrows compound scope, disease categories, and combination-therapy partners.
Therapeutic treatment by contacting or administering a compound with defined structure
A method providing therapeutic treatment to a neoplastic disease, an inflammatory disorder, an autoimmune disorder, a neurodegenerative disease or a metabolic disorder by contacting a cell and/or administering an effective amount of a compound having a structure, including a tautomer or stereoisomer thereof, or a solvate, prodrug or a pharmaceutically acceptable salt thereof, to a subject in need.
Selected compound scope among depicted structures and related forms
The method uses a compound selected from the group consisting of the depicted compounds, including tautomers, stereoisomers, solvates, prodrugs, and pharmaceutically acceptable salts.
Therapeutic indication set for inflammatory and autoimmune disorders
The method is for treating inflammatory or autoimmune disorders including restenosis and other specified inflammatory/autoimmune and related conditions.
Combination therapy with a second therapeutic agent selected from specified drug classes
The method includes a combination therapy wherein the second therapeutic agent is selected from specified classes of anticancer or related drugs, including mitotic inhibitors, vinca alkaloids, vepesid, anthracycline antibiotics, nucleoside analogs, EGFR inhibitors, folate antimetabolites, cisplatin/carboplatin, and HDAC inhibitors.
Combination therapy partner is the nucleoside analog gemcitabine
The method uses gemcitabine as the nucleoside analog for the second therapeutic agent.
Combination therapy partner is an EGFR inhibitor selected from gefitinib or erlotinib
The method uses an EGFR inhibitor as the second therapeutic agent, selected from gefitinib or erlotinib.
Across the independent claim framework, treatment is provided by contacting or administering defined low-cytotoxicity compound structures, including tautomer, stereoisomer, solvate, prodrug, and salt forms. Dependent inventive features narrow the compound set to depicted structures, define broad therapeutic categories including inflammatory and autoimmune disorders, and specify combination therapy with a second agent from constrained anticancer or related drug classes, including gemcitabine and gefitinib or erlotinib as exemplars.
Stated Advantages
Low cytotoxicity.
Compounds block ITCH self-ubiquitination (Lys-dependent) more efficiently than a control compound.
The disclosed compounds demonstrate antiproliferative activity in cell-based assays.
Documented Applications
Therapeutic treatment of cancer.
Therapeutic treatment of autoimmune disorders.
Therapeutic treatment to a neoplastic disease, an inflammatory disorder, an autoimmune disorder, a neurodegenerative disease or a metabolic disorder.
Biological evaluation including inhibition of ITCH self-ubiquitination and associated effects on Lys-dependent polyubiquitylation.
Antiproliferative activity assessment in cell-based assays.
In vivo evaluation in an adjuvant-induced arthritis model with bone mineral density and bone mineral content evaluation.
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