Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation

Xi, Meiyang; Chen, Yi; Yang, Hongyu; Xu, Huiting; Du, Kui; Wu, Chunlei; Xu, Yanfei; Deng, Liping; Luo, Xiang; Yu, Le-Mao; Wu, Yeming; Gao, Xuechuan; Cai, Tao; Chen, Bin; Shen, Runpu; Sun, Haopeng

doi:10.1016/j.ejmech.2019.04.036

Cited by 42 publications

(21 citation statements)

References 124 publications

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“…There are now several reports of small molecules that bind to RAS proteins with high affinity, which should open up new avenues for design of PROTACs (reviewed in Ref. 100).…”

Section: Jbc Reviews: G Protein Ubiquitinationmentioning

confidence: 99%

Regulation of large and small G proteins by ubiquitination

Dohlman

Campbell

2019

Journal of Biological Chemistry

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Edited by Mike Shipston Many sensory and chemical signal inputs are transmitted by intracellular GTP-binding (G) proteins. G proteins make up two major subfamilies: "large" G proteins comprising three subunits and "small" G proteins, such as the proto-oncogene product RAS, which contains a single subunit. Members of both subfamilies are regulated by post-translational modifications, including lipidation, proteolysis, and carboxyl methylation. Emerging studies have shown that these proteins are also modified by ubiquitination. Much of our current understanding of this posttranslational modification comes from investigations of the large G-protein ␣ subunit from yeast (Gpa1) and the three RAS isotypes in humans, NRAS, KRAS, and HRAS. G␣ undergoes both mono-and polyubiquitination, and these modifications have distinct consequences for determining the sites and mechanisms of its degradation. Genetic and biochemical reconstitution studies have revealed the enzymes and binding partners required for addition and removal of ubiquitin, as well as the delivery and destruction of both the mono-and polyubiquitinated forms of the G protein. Complementary studies of RAS have identified multiple ubiquitination sites, each having distinct consequences for binding to regulatory proteins, shuttling to and from the plasma membrane, and degradation. Here, we review what is currently known about these two well-studied examples, Gpa1 and the human RAS proteins, that have revealed additional mechanisms of signal regulation and dysregulation relevant to human physiology. We also compare and contrast the effects of G-protein ubiquitination with other post-translational modifications of these proteins. A variety of sensory and chemical signals are detected by receptors at the cell surface. In many cases, these inputs are transmitted by intracellular GTP-binding proteins (Fig. 1). Generally speaking, large G proteins are activated by seven transmembrane segment receptors, also known as G-proteincoupled receptors (GPCRs). 3 When these receptors bind to an agonist ligand, the G-protein ␣ subunit releases GDP, binds to GTP, and dissociates from the G␤␥ subunit dimer. GTP-bound G␣, G␤␥, or both go on to activate intracellular effectors that transduce the signal. Similarly, many small G proteins are activated by growth factor receptors and their associated guanine nucleotide-exchange factors (GEFs). As with GPCRs, GEFs promote the exchange of GTP for GDP and subsequent activation of downstream effectors. For both large and small G proteins, signaling persists until GTP is converted to GDP, and this inactivation step is accelerated by binding to GTPase-activating proteins (GAPs). Thus, GEFs and GAPs work in opposition to one another to regulate the activity of their cognate G proteins, both large and small. Here, we review newer mechanisms of G-protein regulation by ubiquitination, with a focus on a large G protein from yeast and three small G proteins from humans: NRAS, KRAS, and HRAS. We compare and contrast the effects of ubiquitination with ...

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“…There are now several reports of small molecules that bind to RAS proteins with high affinity, which should open up new avenues for design of PROTACs (reviewed in Ref. 100).…”

Section: Jbc Reviews: G Protein Ubiquitinationmentioning

confidence: 99%

Regulation of large and small G proteins by ubiquitination

Dohlman

Campbell

2019

Journal of Biological Chemistry

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“…The amyloid cross-interactions seem to have a positive effect on the stabilization of the native state and destabilization of incorrectly folded state of amyloids. Thus, by taking inspiration from the heterobifunctional PROTAC approach [248,249] and with the purpose of boosting the positive interaction between two amyloid proteins, two covalently linked protein-binding molecules or peptidomimetics can be designed in this type of protein-protein interaction and exploit as a new therapeutic strategy. The formation of a stable ternary complex between the two amyloids, close together through the PROTAC construct, should improve the approach of the two proteins and allow the natural positive effect of the cross-interaction.…”

Section: Discussionmentioning

confidence: 99%

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

et al. 2020

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Alzheimer’s disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions.

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“…E3-recruiting heterobifunctional degraders E3 recruiting chimeras connect a POI and an E3 ligase to facilitate functional POI ubiquitination [4,5,15]. The ubiquitinated protein is subsequently trafficked to the proteasome for degradation, and the degrader itself is released from the ternary complex where it may cycle through another round of target recruitment (Figure 1A) [4,5].…”

Section: Degrader Typesmentioning

confidence: 99%

Perspectives on the Development of First-in-Class Protein Degraders

2021

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Targeted protein degradation is a broad and expanding field aimed at the modulation of protein homeostasis. A focus of this field has been directed toward molecules that hijack the ubiquitin proteasome system with heterobifunctional ligands that recruit a target protein to an E3 ligase to facilitate polyubiquitination and subsequent degradation by the 26S proteasome. Despite the success of these chimeras toward a number of clinically relevant targets, the ultimate breadth and scope of this approach remains uncertain. Here we highlight recent advances in assays and tools available to evaluate targeted protein degradation, including and beyond the study of E3-targeted chimeric ligands. We note several challenges associated with degrader development and discuss various approaches to expanding the protein homeostasis toolbox.

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Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation

Cited by 42 publications

References 124 publications

Regulation of large and small G proteins by ubiquitination

Regulation of large and small G proteins by ubiquitination

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

Perspectives on the Development of First-in-Class Protein Degraders

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