Compositions and methods for treating EZH2-mediated cancer
Inventors
Jin, Jian • Parsons, Ramon • Stratikopoulos, Ilias • Yang, Xiaobao • Ma, Anqi
Assignees
Icahn School of Medicine at Mount Sinai
Publication Number
US-12274697-B2
Publication Date
2025-04-15
Expiration Date
2037-10-27
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Abstract
Methods for designing bivalent compounds which selectively degrade/disrupt EZH2 and compositions and methods of using such degraders/disruptors to treat EZH2-mediated cancer are provided.
Core Innovation
The invention relates to compositions and methods for administering bivalent compounds that selectively degrade or disrupt enhancer of zeste homologue 2 (EZH2) to treat EZH2-mediated cancers. These bivalent compounds, referred to as EZH2 degraders/disruptors, comprise an EZH2 ligand conjugated to a degradation/disruption tag, linked directly or via a linker, thereby recruiting the ubiquitin-proteasome pathway or mimicking EZH2 misfolding to reduce EZH2 protein levels in cells.
The problem addressed relates to the inadequacy of current EZH2 inhibitors that only inhibit the enzymatic (methyltransferase) activity of EZH2 but do not affect its protein levels. Overexpression of EZH2 drives cancer progression, particularly in breast cancers including triple-negative breast cancer (TNBC), where inhibitors targeting enzymatic activity fail to inhibit cancer growth effectively. The invention aims to overcome this limitation by developing compounds with dual functions of enzyme inhibition and protein degradation/disruption, potentially enhancing therapeutic efficacy.
The disclosure further provides methods to design and identify such bivalent compounds by linking known EZH2 inhibitors or ligands (such as UNC1999, EPZ-6438, GSK126, and others) with degradation/disruption tags (including adamantane, pomalidomide, thalidomide, lenalidomide, or ligands binding ubiquitin ligases like cereblon or VHL). The adapted linkers allow effective conjugation without impairing EZH2 binding, enabling recruitment of the ubiquitination machinery or proteasomal degradation processes to selectively reduce EZH2 protein levels in cancer cells.
Claims Coverage
The patent includes two independent claims covering a class of bivalent compounds for selectively degrading EZH2 and methods of treating EZH2-mediated cancers with such compounds. The main inventive features focus on the structural design of the compounds and their therapeutic application.
Bivalent compound structure with specific degrader/disruption tags and EZH2 ligands
A bivalent compound comprising a degrader/disruption tag selected from adamantane, 1-((4,4,5,5,5-pentafluoropentyl) sulfinyl) nonane, pomalidomide, thalidomide, and VHL-1 conjugated via a linker to an EZH2 ligand selected from specified small-molecule inhibitors and analogs, forming compounds capable of selectively degrading or disrupting EZH2 protein.
Methods for treating EZH2-mediated cancers with bivalent compounds
Administering to a subject having an EZH2-mediated cancer a bivalent compound as defined, where the EZH2-mediated cancers include breast cancer (notably triple-negative breast cancer), glioblastoma, prostate cancer, uterine cancer, ovarian cancer, pancreatic cancer, melanoma, renal cell carcinoma, bladder cancer, colorectal cancer, lymphoma, leukemia, malignant rhabdoid tumor, and oropharyngeal cancer, with potential for cancers overexpressing EZH2 or exhibiting hyper-trimethylated H3K27; administration routes include oral, parenteral, intradermal, subcutaneous, topical, and rectal; methods also optionally include adjunctive cancer therapies such as surgery, chemotherapy, radiation, hormone, or immunotherapy.
The claims protect the composition of bivalent EZH2 degraders/disruptors with defined degradation/disruption tags and EZH2 ligands connected via suitable linkers, as well as methods for treating a broad range of EZH2-mediated cancers using these compounds, highlighting a novel therapeutic approach that targets EZH2 protein for degradation rather than mere enzymatic inhibition.
Stated Advantages
The bivalent compounds possess dual functions of enzymatic EZH2 inhibition plus protein degradation/disruption, which can be significantly more effective therapeutic agents than current EZH2 inhibitors that only inhibit enzymatic activity.
These degraders/disruptors can selectively reduce EZH2 protein levels in cancer cells, potentially overcoming resistance found in cancers with EZH2 overexpression, notably triple-negative breast cancer.
The compounds provide novel treatment options for EZH2-mediated cancers that are refractory or resistant to existing EZH2 enzymatic inhibitors.
Documented Applications
Treatment of EZH2-mediated cancers including breast cancer (especially triple-negative breast cancer), glioblastoma, prostate cancer, uterine cancer, ovarian cancer, pancreatic cancer, melanoma, renal cell carcinoma, bladder cancer, colorectal cancer, lymphoma, leukemia, malignant rhabdoid tumor, and oropharyngeal cancer.
Treatment of relapsed and refractory cancers overexpressing EZH2 or exhibiting hyper-trimethylated H3K27 marks.
Combination therapies with one or more additional cancer treatments including surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.
Methods for identifying bivalent compounds that mediate degradation or disruption of EZH2 by evaluating reduction of EZH2 levels in cells upon treatment.
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