Re-Evaluating the Mechanism of Action of α,β-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs

Ward, Jennifer; Pinto-Fernández, Adán; Cornelissen, Loïc; Bonham, Sarah; Diaz-Saez, L.; Riant, Olivier; Huber, Kilian; Kessler, Benedikt M.; Féron, Olivier; Tate, Edward W.

doi:10.1021/acs.jmedchem.0c00144

Cited by 33 publications

(56 citation statements)

References 35 publications

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“… 48 It was recently reported that total DUB activity in cell lysates is inhibited by 10 and 50 μM b-AP15. 93 The same authors reported inhibition of the activity of different recombinant DUBs using 100 μM b-AP15. This concentration is in the order of >100 times the IC 50 and difficult to interpret.…”

Section: Targets Described For Dienone Compoundsmentioning

confidence: 97%

Dienone Compounds: Targets and Pharmacological Responses

Bazzaro

Linder

2020

J. Med. Chem.

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The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol reactivity, these compounds display considerable degrees of tumor cell selectivity. Here we review in vitro and preclinical studies of dienone compounds including b-AP15, VLX1570, RA-9, RA-190, EF24, HO-3867, and MCB-613. A common property of these compounds is their targeting of the ubiquitin–proteasome system (UPS), known to be essential for the viability of tumor cells. Gene expression profiling experiments have shown induction of responses characteristic of UPS inhibition, and experiments using cellular reporter proteins have shown that proteasome inhibition is associated with cell death. Other mechanisms of action such as reactivation of mutant p53, stimulation of steroid receptor coactivators, and induction of protein cross-linking have also been described. Although unsuitable as biological probes due to widespread reactivity, dienone compounds are cytotoxic to apoptosis-resistant tumor cells and show activity in animal tumor models.

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Section: Targets Described For Dienone Compoundsmentioning

confidence: 97%

Dienone Compounds: Targets and Pharmacological Responses

Bazzaro

Linder

2020

J. Med. Chem.

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“…VLX1570: VLX1570 is an analog of b-AP15 that specifically inhibits USP14 and UCHL5 with improved solubility and potency [ 179 ]. It acts via the disruption of the ubiquitin proteasome degradation pathway, leading to an increase in poly-ubiquitinated proteins, inducible forms of chaperone Hsp70 and other markers characteristic of proteotoxic stress, ER stress, and oxidative stress leading to apoptosis [ 179 , 180 ].…”

Section: Drugs Targeting Dubs In Cancermentioning

confidence: 99%

Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Antao

Tyagi

Kim

et al. 2020

Cancers

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Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

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“…In 2020, Tate and co-workers re-evaluated the mechanism of action of α,β-unsaturated carbonyl compounds as DUB inhibitors [ 95 ], particularly of VLX1570 ( Figure 7 E), a compound that was put on hold in clinical trials after dose-limiting toxicity. Chemical proteomics experiments with an alkyne-tagged derivative of VLX1570 revealed CIAPIN1 as a main protein off-target.…”

Section: Specific Applications Of Bioorthogonal Reactions In Abppmentioning

confidence: 99%

Bioorthogonal Reactions in Activity-Based Protein Profiling

Verhelst

Bonger²,

Willems

2020

Molecules

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Activity-based protein profiling (ABPP) is a powerful technique to label and detect active enzyme species within cell lysates, cells, or whole animals. In the last two decades, a wide variety of applications and experimental read-out techniques have been pursued in order to increase our understanding of physiological and pathological processes, to identify novel drug targets, to evaluate selectivity of drugs, and to image probe targets in cells. Bioorthogonal chemistry has substantially contributed to the field of ABPP, as it allows the introduction of tags, which may be bulky or have unfavorable physicochemical properties, at a late stage in the experiment. In this review, we give an overview of the bioorthogonal reactions that have been implemented in ABPP, provide examples of applications of bioorthogonal chemistry in ABPP, and share some thoughts on future directions.

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Re-Evaluating the Mechanism of Action of α,β-Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs

Cited by 33 publications

References 35 publications

Dienone Compounds: Targets and Pharmacological Responses

Dienone Compounds: Targets and Pharmacological Responses

Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Bioorthogonal Reactions in Activity-Based Protein Profiling

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