Small molecules in targeted cancer therapy: advances, challenges, and future perspectives

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

Published: May 31, 2021

Abstract Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since first tyrosine kinase inhibitor imatinib was approved enter market by US Food Drug Administration (FDA) 2001, an increasing number of small-molecule been developed for treatment malignancies. By December 2020, 89 antitumor FDA National Medical Products (NMPA) China. Despite great progress, anti-cancer still face many challenges, such as a low response rate drug resistance. To better promote development we conducted comprehensive review according target classification. We present all well important candidates clinical trials each target, discuss current provide insights perspectives research drugs.

Language: Английский

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Crystallographic structure of wild-type SARS-CoV-2 main protease acyl-enzyme intermediate with physiological C-terminal autoprocessing site

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Nov. 18, 2020

Abstract Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen that causes disease COVID-19, produces replicase polyproteins 1a and 1ab contain, respectively, 11 or 16 nonstructural proteins (nsp). Nsp5 is main protease (M pro ) responsible for cleavage at eleven positions along these polyproteins, including its own N- C-terminal boundaries, representing essential processing events subsequent viral assembly maturation. We have determined X-ray crystallographic structures of this cysteine in wild-type free active site state 1.8 Å resolution, acyl-enzyme intermediate with native autocleavage sequence 1.95 resolution product bound 2.0 by employing an mutation (C145A). characterize stereochemical features critical hydrogen bonding distances underlying catalysis Cys/His dyad oxyanion hole. also identify a highly ordered water molecule position compatible role as deacylating nucleophile catalytic mechanism binding groove conformational changes dimerization interface occur upon formation acyl-enzyme. Collectively, snapshots provide valuable mechanistic structural insights future antiviral therapeutic development revised molecular docking strategies based on M inhibition.

Language: Английский

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Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models

Frontiers in Cardiovascular Medicine, Journal Year: 2020, Volume and Issue: 7

Published: March 10, 2020

Obesity and diabetes are leading causes of cardiovascular morbidity mortality. Although extensive strides have been made in the treatments for non-diabetic atherosclerosis its complications, patients with diabetes, these therapies provide less benefit protection from disease (CVD). These considerations spur concept that diabetes-specific, disease-modifying essential to identify, especially as epidemics obesity continue expand. Hence, hyperglycemia is a defining feature it logical probe impact specific consequences on vessel wall, immune cell perturbation endothelial dysfunction – all harbingers development CVD. In this context, high levels blood glucose stimulate formation irreversible advanced glycation end products, products nonenzymatic oxidation proteins lipids. AGEs accumulate diabetic circulation tissues interaction their chief cellular receptor, receptor AGE or RAGE, contributes vascular perturbation. The cytoplasmic domain RAGE lacks endogenous kinase activity; discovery intracellular binds formin, DIAPH1, DIAPH1 ligand-mediated signal transduction, identifies means by which functions highlights new target therapeutic interruption signaling. human subjects, prominent signals activity include presence two forms soluble sRAGE secretory (es) RAGE. Further, genetic studies revealed single nucleotide polymorphisms (SNPs) AGER gene (AGER encoding RAGE) display associations This Review presents current knowledge regarding roles Studies both subjects animal models presented highlight breadth evidence linking metabolic disorders.

Language: Английский

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Genome mining methods to discover bioactive natural products

Natural Product Reports, Journal Year: 2021, Volume and Issue: 38(11), P. 2100 - 2129

Published: Jan. 1, 2021

The continual growth of publicly available genomic databases offers researchers unprecedented bioinformatic opportunities. This review examines different approaches to mining data for the targeted discovery bioactive natural products.

Language: Английский

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Molecular Glue Discovery: Current and Future Approaches

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(14), P. 9278 - 9296

Published: July 12, 2023

The intracellular interactions of biomolecules can be maneuvered to redirect signaling, reprogram the cell cycle, or decrease infectivity using only a few dozen atoms. Such "molecular glues," which drive both novel and known between protein partners, represent an enticing therapeutic strategy. Here, we review methods approaches that have led identification small-molecule molecular glues. We first classify current FDA-approved glues facilitate selection discovery methods. then survey two broad method strategies, where highlight importance factors such as experimental conditions, software packages, genetic tools for success. hope this curation methodologies directed will inspire diverse research efforts targeting multitude human diseases.

Language: Английский

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Targeting Tau Protein with Proximity Inducing Modulators: A New Frontier to Combat Tauopathies

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

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NMR as a “Gold Standard” Method in Drug Design and Discovery

Molecules, Journal Year: 2020, Volume and Issue: 25(20), P. 4597 - 4597

Published: Oct. 9, 2020

Studying disease models at the molecular level is vital for drug development in order to improve treatment and prevent a wide range of human pathologies. Microbial infections are still major challenge because pathogens rapidly continually evolve developing resistance. Cancer cells also change genetically, current therapeutic techniques may be (or become) ineffective many cases. The pathology neurological diseases remains an enigma, exact etiology underlying mechanisms largely unknown. Viral spread develop much more quickly than does corresponding research needed combat these infections; present most relevant outbreak SARS-CoV-2, which originated Wuhan, China, illustrates critical immediate need design techniques. Modern day discovery time-consuming, expensive process. Each new takes excess 10 years costs on average billion US dollars. This demonstrates complete redesign or novel strategies. Nuclear Magnetic Resonance (NMR) has played role ever since its introduction several decades ago. In just three decades, NMR become “gold standard” platform technology medical pharmacology studies. this review, we applications spectroscopy development. basic concepts, theories, commonly used presented. We summarize advantages limitations primary methods

Language: Английский

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The design and development of covalent protein-protein interaction inhibitors for cancer treatment

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: March 30, 2020

Abstract Protein-protein interactions (PPIs) are central to a variety of biological processes, and their dysfunction is implicated in the pathogenesis range human diseases, including cancer. Hence, inhibition PPIs has attracted significant attention drug discovery. Covalent inhibitors have been reported achieve high efficiency through forming covalent bonds with cysteine or other nucleophilic residues target protein. Evidence suggests that there reduced risk for development resistance against drugs, which major challenge areas such as oncology infectious diseases. Recent improvements structural biology chemical reactivity enabled design potent selective PPI inhibitors. In this review, we will highlight therapeutic agents targeting cancer therapy.

Language: Английский

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Glycogen Synthase Kinase 3β: A New Gold Rush in Anti-Alzheimer’s Disease Multitarget Drug Discovery?

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 64(1), P. 26 - 41

Published: Dec. 21, 2020

Alzheimer's disease (AD), like other multifactorial diseases, is the result of a systemic breakdown different physiological networks. As result, several lines evidence suggest that it could be more efficiently tackled by molecules directed toward dysregulated biochemical targets or pathways. In this context, selection to which new will crucial. For years, design such multitarget-directed ligands (MTDLs) has been based on main involved in "cholinergic" and "β-amyloid" hypothesis. Recently, there have some reports MTDLs targeting glycogen synthase kinase 3β (GSK-3β) enzyme, due its appealing properties. Indeed, enzyme tau hyperphosphorylation, controls multitude CNS-specific signaling pathways, establishes strict connections with factors implicated AD pathogenesis. present Miniperspective, we discuss reasons behind development GSK-3β-directed highlight recent efforts obtain these classes as potential disease-modifying agents.

Language: Английский

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Computational design of novel protein–protein interactions – An overview on methodological approaches and applications

Current Opinion in Structural Biology, Journal Year: 2022, Volume and Issue: 74, P. 102370 - 102370

Published: April 8, 2022

Protein-protein interactions (PPIs) govern numerous cellular functions in terms of signaling, transport, defense and many others. Designing novel PPIs poses a fundamental challenge to our understanding molecular interactions. The capability robustly engineer has immense potential for the development synthetic biology tools protein-based therapeutics. Over last decades, efforts this area have relied purely on experimental approaches, but more recently, computational protein design made important contributions. Template-based approaches utilize known transplant critical residues onto heterologous scaffolds. De novo instead uses methods generate binding motifs, allowing broader scope sites engaged targets. Here, we review successful cases, giving an overview methodological used templated de PPI design.

Language: Английский

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