Supramolecular artificial Nano-AUTACs enable tumor-specific metabolism protein degradation for synergistic immunotherapy DOI Creative Commons
Yazhen Wang,

Lianyi Yang,

C. Yan

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(25)

Published: June 21, 2024

Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] nucleoside analog methotrexate (MTX) through interactions for tumor-specific protein degradation. Their nanostructures allow precise localization delivery into cancer cells, where intracellular acidic environment disrupt to release MTX eradicating tumor modulating tumor-associated macrophages, activating dendritic inducing autophagy. Specifically, induced autophagy facilitates released degrading immunosuppressive IDO further enhance effector T cell activity inhibit growth metastasis. This study offers unique strategy building nanoplatform advance field in immunotherapy.

Language: Английский

Exploring the next generation of antibody–drug conjugates DOI Open Access
Kyoji Tsuchikama, Yasuaki Anami, Summer Y. Y. Ha

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(3), P. 203 - 223

Published: Jan. 8, 2024

Language: Английский

Citations

174
Precision treatment in advanced hepatocellular carcinoma DOI Creative Commons
Xupeng Yang, Chen Yang, Shu Zhang

et al.

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(2), P. 180 - 197

Published: Feb. 1, 2024

The past decade has witnessed significant advances in the systemic treatment of advanced hepatocellular carcinoma (HCC). Nevertheless, newly developed strategies have not achieved universal success and HCC patients frequently exhibit therapeutic resistance to these therapies. Precision represents a paradigm shift cancer recent years. This approach utilizes unique molecular characteristics individual patient personalize modalities, aiming maximize efficacy while minimizing side effects. Although precision shown multiple types, its application remains infancy. In this review, we discuss key aspects HCC, including biomarkers, classifications, heterogeneity tumor microenvironment. We also propose future directions, ranging from revolutionizing current methodologies personalizing therapy through functional assays, which will accelerate next phase advancements area.

Language: Английский

Citations

118
BRD4-targeted photodegradation nanoplatform for light activatable melanoma therapy DOI

Shiman Lu,

Zhaoqing Shi, Chendi Ding

et al.

Biomaterials, Journal Year: 2025, Volume and Issue: 317, P. 123101 - 123101

Published: Jan. 10, 2025

Language: Английский

Citations

2
Navigating the ERK1/2 MAPK Cascade DOI Creative Commons
Ana Martín-Vega, Melanie H. Cobb

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1555 - 1555

Published: Oct. 20, 2023

The RAS-ERK pathway is a fundamental signaling cascade crucial for many biological processes including proliferation, cell cycle control, growth, and survival; common across all types. Notably, ERK1/2 are implicated in specific context-dependent manner as stem cells pancreatic β-cells. Alterations the different components of this result dysregulation effector kinases which communicate with hundreds substrates. Aberrant activation contributes to range disorders, cancer. This review provides an overview structure, activation, regulation, mutational frequency tiers cascade; particular focus on ERK1/2. We highlight importance scaffold proteins that contribute kinase localization coordinate interaction dynamics substrates, activators, inhibitors. Additionally, we explore innovative therapeutic approaches emphasizing promising avenues field.

Language: Английский

Citations

37
p53/MDM2 signaling pathway in aging, senescence and tumorigenesis DOI
Youyi Huang, Xiaofang Che, Peter Wang

et al.

Seminars in Cancer Biology, Journal Year: 2024, Volume and Issue: 101, P. 44 - 57

Published: May 17, 2024

Language: Английский

Citations

12
Small Molecule Drugs Targeting Viral Polymerases DOI Creative Commons
Deborah Palazzotti,

Martina Sguilla,

Giuseppe Manfroni

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 661 - 661

Published: May 20, 2024

Small molecules that specifically target viral polymerases—crucial enzymes governing genome transcription and replication—play a pivotal role in combating infections. Presently, approved polymerase inhibitors cover nine human viruses, spanning both DNA RNA viruses. This review provides comprehensive analysis of these licensed drugs, encompassing nucleoside/nucleotide (NIs), non-nucleoside (NNIs), mutagenic agents. For each compound, we describe the specific targeted virus related enzyme, mechanism action, relevant bioactivity data. wealth information serves as valuable resource for researchers actively engaged antiviral drug discovery efforts, offering complete overview established strategies well insights shaping development next-generation therapeutics.

Language: Английский

Citations

8
The value of protein allostery in rational anticancer drug design: an update DOI Creative Commons
Ruth Nussinov, Hyunbum Jang

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(9), P. 1071 - 1085

Published: July 28, 2024

Introduction Allosteric drugs are advantageous. However, they still face hurdles, including identification of allosteric sites that will effectively alter the active site. Current strategies largely focus on identifying pockets away from into which ligand dock and do not account for exactly how site is altered. Favorable inhibitors nearby follow nature, mimicking diverse regulation strategies.

Language: Английский

Citations

8
Progress in the development of Macrophage Migration Inhibitory Factor small-molecule inhibitors DOI
Shujin Guo, Yingying Zhao, Yan Yuan

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 286, P. 117280 - 117280

Published: Jan. 13, 2025

Language: Английский

Citations

1
Proactive and reactive roles of TGF-β in cancer DOI Creative Commons
Nick A. Kuburich,

Thiru Sabapathy,

Breanna R. Demestichas

et al.

Seminars in Cancer Biology, Journal Year: 2023, Volume and Issue: 95, P. 120 - 139

Published: Aug. 10, 2023

Cancer cells adapt to varying stress conditions survive through plasticity. Stem exhibit a high degree of plasticity, allowing them generate more stem or differentiate into specialized cell types contribute tissue development, growth, and repair. can also plasticity acquire properties that enhance their survival. TGF-β is an unrivaled growth factor exploited by cancer gain TGF-β-mediated signaling enables carcinoma alter epithelial mesenchymal epithelial-mesenchymal (EMP). However, multifunctional cytokine; thus, the be detrimental beneficial depending on cellular context. Those overcome anti-tumor effect induce transition (EMT) EMP benefits. allows tumor immune microenvironment (TIME), facilitating Due significant roles in progression, it essential understand how exploit this This understanding will guide development effective TGF-β-targeting therapies eliminate

Language: Английский

Citations

22
Revolutionizing Drug Targeting Strategies: Integrating Artificial Intelligence and Structure-Based Methods in PROTAC Development DOI Creative Commons

Mohd Danishuddin,

Mohammad Sarwar Jamal, Kyoung Seob Song

et al.

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(12), P. 1649 - 1649

Published: Nov. 24, 2023

PROteolysis TArgeting Chimera (PROTAC) is an emerging technology in chemical biology and drug discovery. This technique facilitates the complete removal of target proteins that are "undruggable" or challenging to through molecules via Ubiquitin-Proteasome System (UPS). PROTACs have been widely explored outperformed not only cancer but also other diseases. During past few decades, several academic institutes pharma companies poured more efforts into PROTAC-related technologies, setting stage for major degrader trial readouts clinical phases. Despite their promising results, formation robust ternary orientation, off-target activity, poor permeability, binding affinity some limitations hinder development. Recent advancements computational technologies facilitated progress development PROTACs. Researchers able utilize these explore a wider range E3 ligases optimize linkers, thereby gaining better understanding effectiveness safety settings. In this review, we briefly strategies reported date PROTAC components discuss key challenges opportunities further research area.

Language: Английский

Citations

17