Papers by Wayne Fairbrother
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Journal of Back and Musculoskeletal Rehabilitation, May 22, 2003
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ACS Chemical Biology, Sep 1, 2006
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Bioorganic & Medicinal Chemistry Letters, 2012
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Journal of Biological Chemistry, Mar 1, 2002
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ACS Chemical Biology, Oct 1, 2006
Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7, 5]... more Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7, 5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML ...
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ACS Medicinal Chemistry Letters, Sep 8, 2014
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Cell, Sep 1, 2000
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Modulation of proteolysis is an emerging therapeutic mainstay. The clinical success of thalidomid... more Modulation of proteolysis is an emerging therapeutic mainstay. The clinical success of thalidomide and analogs has inspired development of rationally-designed therapeutics that repurpose endogenous degradation machinery to target pathogenic proteins. However, it is unknown whether target removal is the critical effect that drives degrader-induced efficacy. Here we report that proteasome-generated peptides actively initiate degrader-induced cell death. Utilizing BET family degraders as exemplars, we find that induced proteasomal degradation of the BRD4-long isoform (BRD4-L) generates neo-amino-terminal peptides that neutralize Inhibitor of Apoptosis (IAP) proteins to precipitate cell death. Depletion of BRD4-L paradoxically suppresses caspase activation induced by numerous BET degraders. An unbiased screen revealed that other degrader compounds, including clinical CELMoDs, rely on the same mechanism to potentiate caspase activation and apoptosis. Finally, in the context of constituti...
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Cell Death & Disease
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Journal of the American Chemical Society, 2021
We hypothesized that the proximity-driven ubiquitylation of E3-interacting small molecules could ... more We hypothesized that the proximity-driven ubiquitylation of E3-interacting small molecules could affect the degradation of E3 ubiquitin ligases. A series of XIAP BIR2 domain-binding small molecules was modified to append a nucleophilic primary amine. This modification transforms XIAP binders into inducers of XIAP degradation. The degradation of XIAP is E1- and proteasome-dependent, dependent on the ligase function of XIAP, and is rescued by subtle modifications of the small molecule that would obviate ubiquitylation. We demonstrate in vitro ubiquitylation of the small molecule that is dependent on its interaction with XIAP. Taken together, these results demonstrate the designed ubiquitylation of an engineered small molecule and a novel approach for the degradation of E3 ubiquitin ligases.
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Cancer Research, 2007
4736 Starting from a co-crystal structure of the peptide AVPW with ML-IAP, the program CAVEAT was... more 4736 Starting from a co-crystal structure of the peptide AVPW with ML-IAP, the program CAVEAT was used to design potential proline mimetics. The synthesis of an azabicyclooctane core, and incorporation of this core into elaborated antagonists is described. The binding of these compounds to IAP proteins was assessed by fluorescence polarization competition assay, and several compounds with Kis of
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Molecular cell, Jan 15, 2018
Inflammatory responses mediated by NOD2 rely on RIP2 kinase and ubiquitin ligase XIAP for the act... more Inflammatory responses mediated by NOD2 rely on RIP2 kinase and ubiquitin ligase XIAP for the activation of nuclear factor κB (NF-κB), mitogen-activated protein kinases (MAPKs), and cytokine production. Herein, we demonstrate that selective XIAP antagonism blocks NOD2-mediated inflammatory signaling and cytokine production by interfering with XIAP-RIP2 binding, which removes XIAP from its ubiquitination substrate RIP2. We also establish that the kinase activity of RIP2 is dispensable for NOD2 signaling. Rather, the conformation of the RIP2 kinase domain functions to regulate binding to the XIAP-BIR2 domain. Effective RIP2 kinase inhibitors block NOD2 signaling by disrupting RIP2-XIAP interaction. Finally, we identify NOD2 signaling and XIAP-dependent ubiquitination sites on RIP2 and show that mutating these lysine residues adversely affects NOD2 pathway signaling. Overall, these results reveal a critical role for the XIAP-RIP2 interaction in NOD2 inflammatory signaling and provide a...
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Nature, Jan 13, 2016
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Nature, Jan 17, 2015
Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammat... more Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn's disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collecti...
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Papers by Wayne Fairbrother