Targeting the ubiquitin system by fragment-based drug discovery

Kennedy, Cassandra; McPhie, Katherine; Rittinger, Katrin

doi:10.3389/fmolb.2022.1019636

Cited by 8 publications

(6 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…E1 is the least specific component in the Ub system ( 106 ). E1 enzyme activates Ub molecules by consuming ATP, which significantly contributes to occurrence and development process of cancer.…”

Section: Ubiquitin-proteasome System-based Small Molecule Inhibitors/...mentioning

confidence: 99%

The roles of protein ubiquitination in tumorigenesis and targeted drug discovery in lung cancer

Ye,

Yang,

Jiang

et al. 2023

Front. Endocrinol.

View full text Add to dashboard Cite

The malignant lung cancer has a high morbidity rate and very poor 5-year survival rate. About 80% - 90% of protein degradation in human cells is occurred through the ubiquitination enzyme pathway. Ubiquitin ligase (E3) with high specificity plays a crucial role in the ubiquitination process of the target protein, which usually occurs at a lysine residue in a substrate protein. Different ubiquitination forms have different effects on the target proteins. Multiple short chains of ubiquitination residues modify substrate proteins, which are favorable signals for protein degradation. The dynamic balance adapted to physiological needs between ubiquitination and deubiquitination of intracellular proteins is beneficial to the health of the organism. Ubiquitination of proteins has an impact on many biological pathways, and imbalances in these pathways lead to diseases including lung cancer. Ubiquitination of tumor suppressor protein factors or deubiquitination of tumor carcinogen protein factors often lead to the progression of lung cancer. Ubiquitin proteasome system (UPS) is a treasure house for research and development of new cancer drugs for lung cancer, especially targeting proteasome and E3s. The ubiquitination and degradation of oncogene proteins with precise targeting may provide a bright prospect for drug development in lung cancer; Especially proteolytic targeted chimerism (PROTAC)-induced protein degradation technology will offer a new strategy in the discovery and development of new drugs for lung cancer.

show abstract

Section: Ubiquitin-proteasome System-based Small Molecule Inhibitors/...mentioning

confidence: 99%

The roles of protein ubiquitination in tumorigenesis and targeted drug discovery in lung cancer

Ye,

Yang,

Jiang

et al. 2023

Front. Endocrinol.

View full text Add to dashboard Cite

show abstract

“…TPD can be achieved by proteolysis targeting chimera (PROTAC), a method designed to bring an E3 ligase close to the POI for ubiquitination then degradation. PROTAC consists of a E3 ligase-specific ligand and a POI ligand joined by a linker [ 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 ]. Arv-110, Arv-471 and CC-90009 are drugs that utilize the E3 ligase cereblon (CRBN) to degrade specific substrates [ 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 ].…”

Section: Utilizing Multi-functional E3 Ligases For Cancer Therapymentioning

confidence: 99%

RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy

Chang

2023

Biomedicines

View full text Add to dashboard Cite

Ubiquitination is a post-translational modification (PTM) that is involved in proteolysis, protein–protein interaction, and signal transduction. Accumulation of mutations and genomic instability are characteristic of cancer cells, and dysfunction of the ubiquitin pathway can contribute to abnormal cell physiology. Because mutations can be critical for cells, DNA damage repair, cell cycle regulation, and apoptosis are pathways that are in close communication to maintain genomic integrity. Uncontrolled cell proliferation due to abnormal processes is a hallmark of cancer, and mutations, changes in expression levels, and other alterations of ubiquitination factors are often involved. Here, three E3 ubiquitin ligases will be reviewed in detail. RNF126, RNF168 and CUL1 are involved in DNA damage response (DDR), DNA double-strand break (DSB) repair, cell cycle regulation, and ultimately, cancer cell proliferation control. Their involvement in multiple cellular pathways makes them an attractive candidate for cancer-targeting therapy. Functional studies of these E3 ligases have increased over the years, and their significance in cancer is well reported. There are continuous efforts to develop drugs targeting the ubiquitin pathway for anticancer therapy, which opens up the possibility for these E3 ligases to be evaluated for their potential as a target protein for anticancer therapy.

show abstract

“…Various approaches including virtual screening (VS), , high throughput screening (HTS), − and DNA-encoded library (DEL) screening have been used over the years for the discovery of ligands for PPI sites, including those of E3 ligases. , This perspective however focuses specifically on the implementation of fragment-based lead discovery (FBLD) , for the discovery of ligands for E3 ligases. , Despite the accepted challenges of fragment screening for PPI sites, , ligands have been successfully discovered and developed into leads and clinical candidates. Furthermore, ligand discovery has also resulted in chemical tools that have assisted in deciphering the intricate biology of E3 ligases.…”

Section: Introductionmentioning

confidence: 99%

E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology

Michaelides

Collie

2023

J. Med. Chem.

View full text Add to dashboard Cite

Ubiquitination is a key post-translational modification of proteins, affecting the regulation of multiple cellular processes. Cells are equipped with over 600 ubiquitin orchestrators, called E3 ubiquitin ligases, responsible for directing the covalent attachment of ubiquitin to substrate proteins. Due to their regulatory role in cells, significant efforts have been made to discover ligands for E3 ligases. The recent emergence of the proteolysis targeting chimera (PROTAC) and molecular glue degrader (MGD) modalities has further increased interest in E3 ligases as drug targets. This perspective focuses on how fragment based lead discovery (FBLD) methods have been used to discover new ligands for this important target class. In some cases these efforts have led to clinical candidates; in others, they have provided tools for deepening our understanding of E3 ligase biology. Recently, FBLD-derived ligands have inspired the design of PROTACs that are able to artificially modulate protein levels in cells.

show abstract

Targeting the ubiquitin system by fragment-based drug discovery

Cited by 8 publications

References 81 publications

The roles of protein ubiquitination in tumorigenesis and targeted drug discovery in lung cancer

The roles of protein ubiquitination in tumorigenesis and targeted drug discovery in lung cancer

RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy

E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology

Contact Info

Product

Resources

About