Developing Small‐Molecule Inhibitors of HECT‐Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities

Chen, Dan; Gehringer, Matthias; Lorenz, Sonja

doi:10.1002/cbic.201800321

Cited by 29 publications

(25 citation statements)

References 113 publications

(162 reference statements)

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“…Finally, a limited number of small-molecule and peptide inhibitors have been reported for HECT E3s, demonstrating the feasibility of obtaining pharmacological inhibitors for HECT E3s as novel therapeutic approaches to a wide variety of malignancies [79][80][81][82]. However, molecules identified to date have suboptimal pharmacological properties and fall short in terms of potency and specificity and therefore have not been pursued further in clinical research [83].…”

Section: Current Status Of E3 Ligase Therapeutic Developmentmentioning

confidence: 99%

Targeted modulation of E3 ligases using engineered ubiquitin variants

2020

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Ubiquitination plays an essential role in signal transduction to regulate most if not all cellular processes. Among the enzymes that are involved in the ubiquitin (Ub) signaling cascade, tremendous efforts have been focused on elucidating the roles of E3 Ub ligases as they determine the complexity and specificity of ubiquitination. Not surprisingly, the malfunction of E3 ligases is directly implicated in many human diseases, including cancer. Therefore, there is an urgent need to develop potent and specific molecules to modulate E3 ligase activity as intracellular probes for target validation and as pharmacological agents in preclinical research. Unfortunately, the progress has been hampered by the dynamic regulation mechanisms for different types of E3 ligases. Here, we summarize the progress of using protein engineering to develop Ub variant (UbV) inhibitors for all major families of E3 ligases and UbV activators for homologous with E6-associated protein C terminus E3s and homodimeric RING E3s. We believe that this provides a general strategy and a valuable toolkit for the research community to inhibit or activate E3 ligases and these synthetic molecules have important implications in exploring protein degradation for drug discovery.

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Section: Current Status Of E3 Ligase Therapeutic Developmentmentioning

confidence: 99%

Targeted modulation of E3 ligases using engineered ubiquitin variants

2020

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“…As previously described, the regulatory mechanisms of HECT E3s are quite diverse and, therefore, provide a promising opportunity for drug discovery (Chen et al, 2018). Based on the actual knowledge, we can imagine different ways to inhibit their activity, namely: (i) by blocking the binding of the E2 enzymes or adaptor proteins; (ii) by tackling the catalytic cysteine of the enzymes; (iii) by targeting specific regulatory surfaces such as the Ub exosite; (iv) by impairing substrate recognition; and (v) by modulating the oligomeric state (Figure 1).…”

Section: Target Sites and Specificity Of Hect E3 Ligase Inhibitorsmentioning

confidence: 99%

HECT E3 Ligases: A Tale With Multiple Facets

2019

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Ubiquitination plays a pivotal role in several cellular processes and is critical for protein degradation and signaling. E3 ubiquitin ligases are the matchmakers in the ubiquitination cascade, responsible for substrate recognition. In order to achieve selectivity and specificity on their substrates, HECT E3 enzymes are tightly regulated and exert their function in a spatially and temporally controlled fashion in the cells. These characteristics made HECT E3s intriguing targets in drug discovery in the context of cancer biology.

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“…To identify E3 ligases potentially amenable to COFFEE, we used a bioinformatics approach to identify all E3 ligase components containing cysteines. We then filtered out E3 ligases that catalyze direct transfer of ubiquitin from an E2 to the target protein via an active site cysteine, such as HECT E3s, since modification of the reactive cysteine would presumably inhibit E3 ligase activity (Chen et al, 2018). Finally, we prioritized E3 ligases based both on the availability of structural data, and on a low total cysteine count in order to minimize multiple labeling events ( Fig 1A).…”

Section: Electroporation Of Recombinant E3 Ligases Yields Functional mentioning

confidence: 99%

A Strategy to Assess the Cellular Activity of E3 Ligases against Neo-Substrates using Electrophilic Probes

Pinch

Buckley

Gleim

et al. 2020

Preprint

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Targeted protein degradation is a rapidly developing therapeutic modality that promises lower dosing and enhanced selectivity as compared to traditional occupancy-driven inhibitors, and the potential to modulate historically intractable targets. While the well-characterized E3 ligases CRBN and VHL have been successfully redirected to degrade numerous proteins, there are approximately 600 predicted additional E3 family members that may offer improved activity, substrate selectivity, and/or tissue distribution; however, characterizing the potential applications of these many ligases for targeted protein degradation has proven challenging. Here, we report the development of an approach to evaluate the ability of recombinant E3 ligase components to support neo-substrate degradation. Bypassing the need for hit finding to identify specific E3 ligase binders, this approach makes use of simple chemistry for Covalent Functionalization Followed by E3 Electroporation into live cells (COFFEE). We demonstrate this method by electroporating recombinant VHL, covalently functionalized with JQ1 or dasatinib, to induce degradation of BRD4 or kinase targets, respectively. Furthermore, by applying COFFEE to SPSB2, a SOCS box and SPRY-domain E3 ligase that has not previously been redirected for targeted protein degradation, we validate this method as a powerful approach to define the activity of previously uncharacterized ubiquitin ligases against neo-substrates.

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Developing Small‐Molecule Inhibitors of HECT‐Type Ubiquitin Ligases for Therapeutic Applications: Challenges and Opportunities

Cited by 29 publications

References 113 publications

Targeted modulation of E3 ligases using engineered ubiquitin variants

Targeted modulation of E3 ligases using engineered ubiquitin variants

HECT E3 Ligases: A Tale With Multiple Facets

A Strategy to Assess the Cellular Activity of E3 Ligases against Neo-Substrates using Electrophilic Probes

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