Targeted Protein Degraders- The Druggability Perspective DOI Open Access
Satinder Singh, Pratima Srivastava

Journal of Pharmaceutical Sciences, Journal Year: 2023, Volume and Issue: 113(3), P. 539 - 554

Published: Nov. 4, 2023

Language: Английский

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials DOI Creative Commons
Xin Xie, Tingting Yu,

Xiang Li

et al.

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

Published: Sept. 6, 2023

Abstract Undruggable proteins are a class of that often characterized by large, complex structures or functions difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also great opportunity for treatment human diseases and attracted substantial efforts in the field medicine. Therefore, this review, we focus on recent development discovery targeting “undruggable” their application clinic. To make review well organized, discuss strategies proteins, including covalent regulation, allosteric inhibition, protein–protein/DNA interaction targeted nucleic acid-based approach, immunotherapy others.

Language: Английский

Citations

154
Expanding the horizons of targeted protein degradation: A non-small molecule perspective DOI Creative Commons
Xiaowei Huang, Fengbo Wu,

Jing Ye

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2402 - 2427

Published: Jan. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Language: Английский

Citations

16
Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies DOI Creative Commons
Elisa Uliassi, María Laura Bolognesi, Andrea Milelli

et al.

ACS Pharmacology & Translational Science, Journal Year: 2025, Volume and Issue: 8(3), P. 654 - 672

Published: Feb. 10, 2025

Dysregulation of correct protein tau homeostasis represents the seed for development several devastating central nervous system disorders, known as tauopathies, that affect millions people worldwide. Despite massive public and private support to research funding, these diseases still represent unmet medical needs. In fact, tau-targeting tools developed date have failed translate into clinic. Recently, taking advantage modes nature uses mediate flow information in cells, researchers a new class molecules, called proximity-inducing modulators, which exploit spatial proximity modulate function(s) redirect cellular processes. this perspective, after brief discussion about classic approaches, we will discuss different classes modulators so far highlight applications protein's function tau-induced toxicity.

Language: Английский

Citations

2
Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies DOI Creative Commons

Wei‐Fang Zuo,

Qiwen Pang, Xinyu Zhu

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Sept. 4, 2024

Language: Английский

Citations

10
Targeted protein degradation in drug development: Recent advances and future challenges DOI
Jian H. Song, Mingzheng Hu, Jun Zhou

et al.

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 261, P. 115839 - 115839

Published: Sept. 27, 2023

Language: Английский

Citations

17
Autophagy modulation in cancer therapy: Challenges coexist with opportunities DOI
Yongya Wu,

Aoxue Wang,

Guotai Feng

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 276, P. 116688 - 116688

Published: July 17, 2024

Language: Английский

Citations

5
Metal-free assembly of diverse polysubstituted pyridines via an efficient cascade approach using tertiary enaminones and α,β-unsaturated sulfonylketimines DOI

Xiang Li,

Qiwen Pang, Yang Zhang

et al.

Organic Chemistry Frontiers, Journal Year: 2024, Volume and Issue: 11(9), P. 2607 - 2612

Published: Jan. 1, 2024

A metal-free, scalable, and cascade protocol for assembling diverse polysubstituted pyridines from tertiary enaminones α,β-unsaturated sulfonylketimines by cleaving C–N/N–S bonds is reported.

Language: Английский

Citations

4
Exploration of Degrons and Their Ability to Mediate Targeted Protein Degradation DOI
Timothy J. Harris, Darci J. Trader

RSC Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Degrons are regions of a protein that required to initiate their degradation by cellular machinery.

Language: Английский

Citations

0
Harnessing Natural Saponins: Advancements in Mitochondrial Dysfunction and Therapeutic Applications DOI

Hongmei Liu,

Huan Wang, Xinyu Lin

et al.

Phytomedicine, Journal Year: 2025, Volume and Issue: 138, P. 156383 - 156383

Published: Jan. 10, 2025

Language: Английский

Citations

0
Targeted Protein Degradation in Cancer Therapy via Hydrophobic Polymer-Tagged Nanoparticles DOI
Seohee Lee, Seonwoo Kang, Won Jong Kim

et al.

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Targeted protein degradation (TPD) strategies offer a significant advantage over traditional small molecule inhibitors by selectively degrading disease-causing proteins. While molecules can lead to recurrence and resistance due compensatory pathway activation, TPD addresses this limitation promoting degradation, thereby reducing the likelihood of long-term. Despite these benefits, bifunctional face challenges such as low solubility, poor bioavailability, limited tumor specificity. In study, we developed polymer-based nanoparticles that combine with nanotechnology through hydrophobic tagging method. Hydrophobic polymer-tagged facilitate targeted incorporating polymers mimic residues in misfolded This system combines delivery capabilities within platform, inducing while improving stability, targeting. These consist block copolymer composed an androgen receptor ligand (ARL)-conjugated polylactic acid (PLA) hydrophilic polyethylene glycol (PEG), connected GSH-cleavable disulfide bond. aqueous solutions, (ARL-PLA-SS-PEG) forms micelles degrade reducible cellular environments. The demonstrated vitro target (AR). Furthermore, they achieved substantial accumulation significantly inhibited growth tumor-bearing mouse model. A mechanistic study revealed micelle-mediated follows dual involving both proteasome autophagosome. approach has potential serve universal platform for eliminating need develop disease-specific molecules.

Language: Английский

Citations

0