Injecting hope: the potential of intratumoral immunotherapy for locally advanced and metastatic cancer DOI Creative Commons
Markéta Skaličková, Katerina Hadrava Vanova, Ondřej Uher

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 9, 2025

Despite enormous progress, advanced cancers are still one of the most serious medical problems in current society. Although various agents and therapeutic strategies with anticancer activity known used, they often fail to achieve satisfactory long-term patient outcomes survival. Recently, immunotherapy has shown success patients by harnessing important interactions between immune system cancer. However, many these therapies lead frequent side effects when administered systemically, prompting treatment modifications or discontinuation or, severe cases, fatalities. New approaches like intratumoral immunotherapy, characterized reduced effects, cost, systemic toxicity, offer promising prospects for future applications clinical oncology. In context locally metastatic cancer, combining diverse immunotherapeutic other targeting multiple cancer hallmarks appears crucial. Such combination hold promise improving survival promoting a sustained response. This review aims provide overview approaches, specifically focusing on administration drugs cancers. It also explores integration modalities maximize Additionally, summarizes recent advances discusses novel outlining directions field.

Language: Английский

Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic DOI Creative Commons
Janet M. Sasso,

Rumiana Tenchov,

Dasheng Wang

et al.

Biochemistry, Journal Year: 2022, Volume and Issue: 62(3), P. 601 - 623

Published: July 20, 2022

Targeted protein degradation is a rapidly exploding drug discovery strategy that uses small molecules to recruit disease-causing proteins for rapid destruction mainly via the ubiquitin-proteasome pathway. It shows great potential treating diseases such as cancer and infectious, inflammatory, neurodegenerative diseases, especially those with "undruggable" pathogenic targets. With recent rise of "molecular glue" type degraders, which tighten simplify connection an E3 ligase ubiquitination subsequent degradation, new therapies unmet medical needs are being designed developed. Here we use data from CAS Content Collection publication landscape research on targeted degraders provide insights into these molecules, special focus molecular glues. We also outline advantages glues summarize advances in practices glue degraders. further thorough review candidates through recruitment. Finally, highlight progression pipelines their diseases. Overall, our paper provides comprehensive reference support future development medicine.

Language: Английский

Citations

112
Targeted protein degradation: from mechanisms to clinic DOI
Jonathan M. Tsai, Radosław P. Nowak, Benjamin L. Ebert

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(9), P. 740 - 757

Published: April 29, 2024

Language: Английский

Citations

98
Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology DOI
Carmine Settembre, Rushika M. Perera

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(3), P. 223 - 245

Published: Nov. 24, 2023

Language: Английский

Citations

95
Proximity-Based Modalities for Biology and Medicine DOI Creative Commons
Xingui Liu, Alessio Ciulli

ACS Central Science, Journal Year: 2023, Volume and Issue: 9(7), P. 1269 - 1284

Published: July 14, 2023

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of processes high selectivity has the potential to substantially expand target space. A plethora proximity-based modalities proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines mechanisms molecules based on induced proximity, including protein degraders, blockers, stabilizers, inducers post-translational modifications, agents cell therapy, discusses challenges that field must address mature unlock translation in biology medicine.

Language: Английский

Citations

89
Emerging degrader technologies engaging lysosomal pathways DOI Creative Commons
Yu Ding, Dong Xing, Yiyan Fei

et al.

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(21), P. 8832 - 8876

Published: Jan. 1, 2022

ATTECs and several other emerging degrader technologies hijacking the lysosomal pathways greatly expand spectrum of degradable targets provide new opportunities for targeted drug discovery.

Language: Английский

Citations

79
Bifunctional Compounds as Molecular Degraders for Integrin-Facilitated Targeted Protein Degradation DOI
Jiwei Zheng,

Wanyi He,

Jing Li

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(48), P. 21831 - 21836

Published: Nov. 23, 2022

As effective ways to regulate protein levels, targeted degradation technologies have attracted great attention in recent years. Here, we established a novel integrin-facilitated lysosomal (IFLD) strategy degrade extracellular and cell membrane proteins using bifunctional compounds as molecular degraders. By conjugation of target protein-binding ligand with an integrin-recognition ligand, the resulting degrader proved be highly efficient induce internalization subsequent or integrin- lysosome-dependent manner. demonstrated development BMS-L1-RGD, which is programmed death-ligand 1 (PD-L1) validated both vitro vivo, IFLD expands toolbox for regulation secreted membrane-associated thus has potential applied chemical biology drug discovery.

Language: Английский

Citations

77
The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics DOI
Linghui Qian,

Xuefen Lin,

Xue Gao

et al.

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(12), P. 7782 - 7853

Published: May 15, 2023

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, basic research. A plethora chemical genetic approaches been devised to make accessible more "undruggable" targets equipped with new functions illustrating or regulating biological processes precisely. In this Review, addition introducing how naked various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide antibody-enzyme etc.) work therapeutic applications, special attention has paid chemistry tools helped optimize the outcome (i.e., enhanced efficacy reduced side effects) facilitate multifunctionalization antibodies, focus on emerging fields such targeted protein degradation, real-time live-cell imaging, catalytic labeling decaging spatiotemporal control well engagement inside cells. With advances modern biotechnology, well-designed derivatives via size miniaturization together efficient delivery systems emerged, which gradually improved our understanding important paved way pursue novel for potential treatments diseases.

Language: Английский

Citations

68
Extracellular targeted protein degradation: an emerging modality for drug discovery DOI
James A. Wells, Kaan Kumru

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 23(2), P. 126 - 140

Published: Dec. 7, 2023

Language: Английский

Citations

67
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

43
Targeted protein degradation directly engaging lysosomes or proteasomes DOI Creative Commons
Jiseong Kim, Insuk Byun, Do Young Kim

et al.

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(7), P. 3253 - 3272

Published: Jan. 1, 2024

This review delineates emerging technologies for targeted protein degradation that directly involve lysosomes or proteasomes. It explores their unique features, advantages, and limitations, offering perspectives on future therapeutic applications.

Language: Английский

Citations

28