Targeted protein degradation: mechanisms, strategies and application

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: April 4, 2022

Abstract Traditional drug discovery mainly focuses on direct regulation of protein activity. The development and application activity modulators, particularly inhibitors, has been the mainstream in development. In recent years, PROteolysis TArgeting Chimeras (PROTAC) technology emerged as one most promising approaches to remove specific disease-associated proteins by exploiting cells’ own destruction machinery. addition PROTAC, many different targeted degradation (TPD) strategies including, but not limited to, molecular glue, Lysosome-Targeting Chimaera (LYTAC), Antibody-based PROTAC (AbTAC), are emerging. These technologies have only greatly expanded scope TPD, also provided fresh insights into discovery. Here, we summarize advances major TPD technologies, discuss their potential applications, hope provide a prime for both biologists chemists who interested this vibrant field.

Language: Английский

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Targeting p53 pathways: mechanisms, structures and advances in therapy

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 1, 2023

The TP53 tumor suppressor is the most frequently altered gene in human cancers, and has been a major focus of oncology research. p53 protein transcription factor that can activate expression multiple target genes plays critical roles regulating cell cycle, apoptosis, genomic stability, widely regarded as "guardian genome". Accumulating evidence shown also regulates metabolism, ferroptosis, microenvironment, autophagy so on, all which contribute to suppression. Mutations not only impair its function, but confer oncogenic properties mutants. Since mutated inactivated malignant tumors, it very attractive for developing new anti-cancer drugs. However, until recently, was considered an "undruggable" little progress made with p53-targeted therapies. Here, we provide systematic review diverse molecular mechanisms signaling pathway how mutations impact progression. We discuss key structural features inactivation by mutations. In addition, efforts have therapies, challenges encountered clinical development.

Language: Английский

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The role of ubiquitination and deubiquitination in cancer metabolism

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Oct. 1, 2020

Abstract Metabolic reprogramming, including enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance redox homeostasis, is considered a hallmark cancer, sustaining cancer cell growth. Multiple signaling pathways, transcription factors metabolic enzymes participate in the modulation metabolism thus, reprogramming highly complex process. Recent studies have observed that ubiquitination deubiquitination are involved regulation cells. As one most important type post-translational modifications, multistep enzymatic process, diverse cellular biological activities. Dysregulation contributes to various disease, cancer. Here, we discuss role which aimed at highlighting importance this modification supporting development new therapeutic approaches for treatment.

Language: Английский

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Integrated analysis of single-cell and bulk RNA sequencing data reveals a pan-cancer stemness signature predicting immunotherapy response

Genome Medicine, Journal Year: 2022, Volume and Issue: 14(1)

Published: April 29, 2022

Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only limited fraction of patients benefit from it. Cancer stemness can be the potential culprit ICI resistance, but direct clinical evidence lacking.

Language: Английский

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Integration of multiomics data with graph convolutional networks to identify new cancer genes and their associated molecular mechanisms

Nature Machine Intelligence, Journal Year: 2021, Volume and Issue: 3(6), P. 513 - 526

Published: April 12, 2021

Language: Английский

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Cytosolic DNA sensing by cGAS: regulation, function, and human diseases

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: April 30, 2021

Abstract Sensing invasive cytosolic DNA is an integral component of innate immunity. cGAS was identified in 2013 as the major sensor that binds dsDNA to catalyze synthesis a special asymmetric cyclic-dinucleotide, 2′3′-cGAMP, secondary messenger bind and activate STING for subsequent production type I interferons other immune-modulatory genes. Hyperactivation signaling contributes autoimmune diseases but serves adjuvant anticancer immune therapy. On hand, inactivation causes deficiency sense clear viral bacterial infection creates tumor-prone microenvironment facilitate tumor evasion surveillance. Thus, activation tightly controlled. In this review, we summarize up-to-date multilayers regulatory mechanisms governing activation, including pre- post-translational regulations, cGAS-binding proteins, additional regulators such ions small molecules. We will also reveal pathophysiological function its product cGAMP human diseases. hope provide review recent research advances biology cGAS-targeted therapies

Language: Английский

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Posttranslational Modifications in Ferroptosis

Oxidative Medicine and Cellular Longevity, Journal Year: 2020, Volume and Issue: 2020, P. 1 - 12

Published: Nov. 26, 2020

Ferroptosis was first coined in 2012 to describe the form of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation. To date, ferroptosis has been implicated many diseases, such as carcinogenesis, degenerative diseases (e.g., Huntington’s, Alzheimer’s, and Parkinson’s diseases), ischemia-reperfusion injury, cardiovascular diseases. Previous studies have identified numerous targets involved ferroptosis; for example, acyl-CoA synthetase long-chain family member 4 (ACSL4) p53 induce while glutathione peroxidase (GPX4) apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known FSP1) inhibit ferroptosis. At least three major pathways (the glutathione-GPX4, FSP1-coenzyme Q10 (CoQ10), GTP cyclohydrolase-1- (GCH1-) tetrahydrobiopterin (BH4) pathways) participate regulation. Recent advances highlighted crucial roles posttranslational modifications (PTMs) proteins Here, we summarize recently discovered knowledge regarding mechanisms underlying ferroptosis, particularly PTMs

Language: Английский

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Pathological implication of protein post-translational modifications in cancer

Molecular Aspects of Medicine, Journal Year: 2022, Volume and Issue: 86, P. 101097 - 101097

Published: April 7, 2022

Language: Английский

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Ubiquitin ligases: guardians of mammalian development

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(5), P. 350 - 367

Published: Jan. 25, 2022

Language: Английский

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The role of ubiquitination and deubiquitination in tumor invasion and metastasis

International Journal of Biological Sciences, Journal Year: 2022, Volume and Issue: 18(6), P. 2292 - 2303

Published: Jan. 1, 2022

Ubiquitination is vital for multiple cellular processes via dynamic modulation of proteins related to cell growth, proliferation, and survival.Of the ubiquitination system components, E3 ubiquitin ligases deubiquitinases have most prominent roles in modulating tumor metastasis.This review will briefly summarize observations underlying mechanisms regulate metastasis.Further, we discuss relationship importance between components progression.

Language: Английский

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