Inhibitors of the linear ubiquitin chain assembly complex (LUBAC) and related methods
Inventors
Staudt, Louis M. • Yang, Yibin • Bernal, Federico • Whiting, Amanda L.
Assignees
US Department of Health and Human Services
Publication Number
US-9783586-B2
Publication Date
2017-10-10
Expiration Date
2034-03-11
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Abstract
The invention relates to peptide inhibitors of linear ubiquitin chain assembly complex (LUBAC) and to methods of treating diseases including activated B-cell like diffuse large B cell lymphoma (ABC DLBCL) and autoimmune or inflammatory disorders.
Core Innovation
The invention relates to peptide inhibitors of the linear ubiquitin chain assembly complex (LUBAC) and methods of treating diseases associated with LUBAC activation of NF-κB signaling. The peptide inhibitors are based on the RNF31 (HOIP) sequence 606-628 (SEQ ID NO: 1) and include modified variants and hydrocarbon-stapled α-helical peptides designed to disrupt LUBAC activity, especially by interfering with LUBAC complex formation via inhibition of the RNF31-RBCK1 interaction. These peptides are cell-permeable and useful for inhibiting LUBAC in vitro and in vivo.
The problem addressed is the dysregulation of NF-κB signaling in diseases such as activated B-cell like diffuse large B cell lymphoma (ABC DLBCL) and autoimmune or inflammatory disorders. LUBAC plays a role in linear ubiquitination necessary for canonical NF-κB activation. Existing knowledge showed difficulties inhibiting LUBAC via larger fragments of RNF31, so there was a need for therapeutics that selectively inhibit LUBAC to treat diseases with NF-κB dysregulation.
The invention further identifies that LUBAC inhibition is selectively cytotoxic to ABC DLBCL cells, with peptide inhibitors able to disrupt NF-κB signaling by impairing LUBAC function. Methods of treatment include administering these peptide inhibitors alone or in combination with other therapeutic agents such as chemotherapeutic or radiological agents. The invention also covers methods of sensitizing ABC DLBCL to cytotoxic therapies by administering LUBAC inhibitors.
Claims Coverage
The claims include multiple independent claims covering cell permeable peptide inhibitors of LUBAC and methods of treating ABC DLBCL and related diseases. The main inventive features relate to the peptide sequences, modifications, and therapeutic uses.
Cell permeable peptide inhibitors comprising modified RNF31 sequences
Peptides comprising any one of SEQ ID NOs: 2-16 or SEQ ID NO: 20 having 45 amino acids or fewer, optionally including amino protecting groups, carboxylic acid protecting groups, linkers, and non-proteogenic amino acids, with no additional amino acids outside these modifications.
Peptides including non-natural amino acid substitutions or insertions
Peptides with hydrocarbon staples or cross-links formed by non-natural amino acids such as (S)-pentenylalanine positioned to stabilize α-helical structure and enhance cell permeability and function.
Methods of treating ABC DLBCL by administering effective amounts of peptide inhibitors
Therapeutic methods comprising administration of the peptide inhibitors to subjects suffering from or at risk for ABC DLBCL, optionally in combination with chemotherapy or radiation.
Methods of killing ABC DLBCL cells via peptide inhibitors
In vitro or in vivo methods of killing ABC DLBCL cells by administering compositions comprising the specified peptide inhibitors, optionally combined with chemotherapeutic or radiotherapeutic agents.
Methods of treating autoimmune and inflammatory disorders with peptide inhibitors
Treatment of rheumatoid arthritis, chronic autoinflammation, systemic lupus erythematosus, Crohn’s inflammatory bowel disease, psoriasis, and related conditions by administering effective amounts of the specified peptide inhibitors.
Methods of treating therapy-resistant cancers using peptide inhibitors
Treatment methods for cancers resistant to cytotoxic chemotherapy, radiation therapy, vaccine therapy, or cytokine therapy by administration of the peptide inhibitors, potentially combined with other therapeutic agents.
The claims protect cell-permeable, stapled peptide inhibitors based on modified RNF31 sequences that inhibit LUBAC by disrupting protein interactions, methods of using these peptides to treat ABC DLBCL and autoimmune/inflammatory diseases, and methods of killing ABC DLBCL cells with or without adjunct therapies.
Stated Advantages
The peptide inhibitors are selectively cytotoxic to activated B-cell like diffuse large B cell lymphoma (ABC DLBCL), sparing germinal center B cell-like (GCB) DLBCL cells.
The stapled peptides are cell-permeable, which enhances their utility in vitro and in vivo treatments.
The inhibitors disrupt LUBAC complex formation, thereby effectively inhibiting NF-κB signaling implicated in oncogenic survival pathways.
Use of LUBAC peptide inhibitors can sensitize ABC DLBCL cells to cytotoxic chemotherapy and radiation therapy.
Documented Applications
Treatment of activated B-cell like diffuse large B cell lymphoma (ABC DLBCL) by administering peptide inhibitors of LUBAC.
Methods for killing ABC DLBCL cells in vitro or in vivo using peptide inhibitors.
Treatment of autoimmune or inflammatory disorders such as rheumatoid arthritis, chronic autoinflammation, systemic lupus erythematosus, Crohn's inflammatory bowel disease, and psoriasis.
Treatment of cancers resistant to cytotoxic chemotherapy, radiation therapy, vaccine therapy, or cytokine therapy using LUBAC peptide inhibitors.
Screening methods to identify cancer patients likely to benefit from treatment with LUBAC inhibitors by testing biopsy samples with peptide inhibitors and therapeutic agents.
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