Expanding the landscape of E3 ligases for targeted protein degradation

Kramer, Luke T.; Zhang, Xiaoyu

doi:10.1016/j.crchbi.2022.100020

Cited by 29 publications

(22 citation statements)

References 27 publications

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“…There are about 600 E3 ligases, in three major families: RING/U-box, HECT, and RING-Between-RING (RBR) [ 56 , 57 , 58 , 59 ]. However, most PROTACs utilize only CRBN or VHL E3 ligases, which may be disadvantageous due to E3 ligase mutations rendering them unable to engage in PROTAC activity [ 60 ]. Moreover, the expression of E3 ligases is tissue-specific and even varies between different cell metabolic stages.…”

Section: Proteolysis-targeting Chimeras (Protacs) and Snipersmentioning

confidence: 99%

“…Tailoring PROTACs to a specific E3 ligase profile in a given cell target may perhaps facilitate their efficacy. Alternative E3 ligases with known ligands include mouse double minute 2 homolog (MDM2), cellular inhibitor of apoptosis protein-1 (cIAP1), X-linked inhibitor of apoptosis protein (XIAP), aryl hydrocarbon receptor (AhR), Kelch-like ECH-associated protein 1(KEAP1), and DDB1 and CUL4 associated factor 15 (DCAF15) [ 60 ]. The recognition of the substrate is guided by specific motifs called degrons, i.e., a free N-terminal amino acid (N-degron), C-degron, or hydroxylated proline residue in the Hypoxia-Inducible Factor 1 α (HIF1α).…”

Section: Proteolysis-targeting Chimeras (Protacs) and Snipersmentioning

confidence: 99%

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Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

Wolska-Washer

Smolewski

2022

Cancers

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Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studies have led to the development of proteasome inhibitors, which have advanced into drugs (such as bortezomib) used in the treatment of certain hematological tumors, including multiple myeloma. New therapeutic options have been studied making use of the so-called proteolysis-targeting chimeras (PROTACs), that bind desired proteins with a linker that connects them to an E3 ubiquitin ligase, resulting in proteasomal-targeted degradation. This review examines the mechanisms of protein degradation in the cells of the hematopoietic system, explains the role of dysfunctional protein degradation in the pathogenesis of hematological malignancies, and discusses the current and future advances of therapies targeting these pathways, based on an extensive search of the articles and conference proceedings from 2005 to April 2022.

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Section: Proteolysis-targeting Chimeras (Protacs) and Snipersmentioning

confidence: 99%

Section: Proteolysis-targeting Chimeras (Protacs) and Snipersmentioning

confidence: 99%

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

Wolska-Washer

Smolewski

2022

Cancers

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“…This however could be ensured by alternative E3 ligases. Among those are MDM2, DCAF15, DCAF16, RNF4, RNF114, FEM1B, KEAP1, AhR, cIAP1 and XIAP, which pose several distinct advantages including specificity for tissue, tumor, cell type or cell state, and synergistic tumoricidial effects through activation of pro-apoptotic cell cycle regulatory proteins [ 54 ].…”

Section: Targeted Protein Degradation Approachesmentioning

confidence: 99%

Targeted Protein Degradation: Clinical Advances in the Field of Oncology

Salama¹,

Trkulja²,

Casanova³

et al. 2022

IJMS

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The field of targeted protein degradation (TPD) is a rapidly developing therapeutic modality with the promise to tame disease-relevant proteins in ways that are difficult or impossible to tackle with other strategies. While we move into the third decade of TPD, multiple degrader drugs have entered the stage of the clinic and many more are expected to follow. In this review, we provide an update on the most recent advances in the field of targeted degradation with insights into possible clinical implications for cancer prevention and treatment.

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“…Degraders are typically categorized either as heterobifunctional PROTACs, or as monovalent molecular glues. Many of the E3 ligases that are currently amenable to TPD are members of the large family of cullin RING E3 ubiquitin ligases (CRL) [4][5][6] . CRLs are modular protein assemblies that are organized around a central cullin backbone.…”

Section: Introductionmentioning

confidence: 99%

Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders

et al. 2022

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Targeted protein degradation is a novel pharmacology established by drugs that recruit target proteins to E3 ubiquitin ligases. Based on the structure of the degrader and the target, different E3 interfaces are critically involved, thus forming defined "functional hotspots". Understanding disruptive mutations in functional hotspots informs on the architecture of the assembly, and highlights residues susceptible to acquire resistance phenotypes. Here, we employ haploid genetics to show that hotspot mutations cluster in substrate receptors of hijacked ligases, where mutation type and frequency correlate with gene essentiality. Intersection with deep mutational scanning revealed hotspots that are conserved or specific for chemically distinct degraders and targets. Biophysical and structural validation suggests that hotspot mutations frequently converge on altered ternary complex assembly. Moreover, we validated hotspots mutated in patients that relapse from degrader treatment. In sum, we present a fast and widely accessible methodology to characterize small-molecule degraders and associated resistance mechanisms.

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Expanding the landscape of E3 ligases for targeted protein degradation

Cited by 29 publications

References 27 publications

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies

Targeted Protein Degradation: Clinical Advances in the Field of Oncology

Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders

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