Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders

Chemical Society Reviews, Год журнала: 2022, Номер 51(19), С. 8216 - 8257

Опубликована: Янв. 1, 2022

This review provides a comprehensive overview of the structure-based design small-molecule VHL ligands and their applications as inhibitors E3 ligase recruiting moieties in PROTAC degraders.

Язык: Английский

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G Protein–Coupled Estrogen Receptor GPER: Molecular Pharmacology and Therapeutic Applications

The Annual Review of Pharmacology and Toxicology, Год журнала: 2023, Номер 63(1), С. 295 - 320

Опубликована: Янв. 20, 2023

The actions of estrogens and related estrogenic molecules are complex multifaceted in both sexes. A wide array natural, synthetic, therapeutic target pathways that produce respond to estrogens. Multiple receptors promulgate these responses, including the classical estrogen nuclear hormone receptor family (estrogen α β), which function largely as ligand-activated transcription factors, 7-transmembrane G protein–coupled receptor, GPER, activates a diverse signaling pathways. pharmacology functional roles GPER physiology disease reveal important responses natural synthetic compounds numerous physiological systems. These functions have implications treatment myriad states, cancer, cardiovascular diseases, metabolic disorders. This review focuses on summarizes major ongoing applications GPER-targeted compounds.

Язык: Английский

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New-generation advanced PROTACs as potential therapeutic agents in cancer therapy

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Май 21, 2024

Abstract Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit endogenous E3 ubiquitin ligases facilitate degradation of interest (POIs) through ubiquitin–proteasome system (UPS) in cyclic catalytic manner. Despite recent endeavors advance utilization clinical settings, majority fail progress beyond preclinical phase drug development. There are multiple factors impeding market entry PROTACs, insufficiently precise favorable POIs standing out as one most formidable obstacles. Recently, there been exploration new-generation advanced including PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, improve vivo efficacy PROTACs. These improved possess capability mitigate undesirable physicochemical characteristics inherent thereby enhancing their targetability reducing off-target side effects. The will mark pivotal turning point realm targeted protein degradation. In this comprehensive review, we meticulously summarized state-of-the-art advancements achieved by these cutting-edge elucidated underlying design principles, deliberated upon prevailing encountered, provided an insightful outlook on future prospects within field.

Язык: Английский

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Progress and Challenges in Targeted Protein Degradation for Neurodegenerative Disease Therapy

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(17), С. 11454 - 11477

Опубликована: Авг. 25, 2022

Neurodegenerative diseases (NDs) are currently incurable that cause progressive degeneration of nerve cells. Many the disease-causing proteins NDs "undruggable" for traditional small-molecule inhibitors (SMIs). None compounds attenuated amyloid-β (Aβ) accumulation process have entered clinical practice, and many phase III trials SMIs Alzheimer's disease (AD) failed. In recent years, emerging targeted protein degradation (TPD) technologies such as proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimaeras (LYTACs), autophagy-targeting (AUTACs) with TPD-assistive click-formed (CLIPTACs) deubiquitinase-targeting chimera (DUBTAC) developed rapidly. vitro in vivo experiments also confirmed TPD technology can target ND pathogenic proteins, bringing hope treatment NDs. Herein, we review latest technologies, introduce their targets technical characteristics, discuss potential research, providing a new perspective development field.

Язык: Английский

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Systematic Potency and Property Assessment of VHL Ligands and Implications on PROTAC Design

ChemMedChem, Год журнала: 2023, Номер 18(8)

Опубликована: Фев. 7, 2023

Herein, we describe a systematic SAR- and SPR-investigation of the peptidomimetic hydroxy-proline based VHL-ligand VH032, from which most to-date published VHL-targeting PROTACs have been derived. This study provides for first time consistent data set allows direct comparison structural variations including those were so far hidden in patent literature. The gained knowledge about improved VHL binders was used to design small library highly potent BRD4-degraders comprising different exit vectors. Newly designed degraders showed favorable molecular properties significantly degradation potency compared MZ1.

Язык: Английский

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PROTACs: A novel strategy for cancer drug discovery and development

MedComm, Год журнала: 2023, Номер 4(3)

Опубликована: Май 29, 2023

Proteolysis targeting chimera (PROTAC) technology has become a powerful strategy in drug discovery, especially for undruggable targets/proteins. A typical PROTAC degrader consists of three components: small molecule that binds to target protein, an E3 ligase ligand (consisting and its recruiter), chemical linker hooks first two components together. In the past 20 years, we have witnessed advancement multiple degraders into clinical trials anticancer therapies. However, one major challenges is only very limited number recruiters are currently available as targeted protein degradation (TPD), although human genome encodes more than 600 ligases. Thus, there urgent need identify additional effective TPD applications. this review, summarized existing RING-type ubiquitin their act ligands application discovery. We believe review could serve reference future development efficient cancer discovery development.

Язык: Английский

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PROTAC-biomacromolecule conjugates for precise protein degradation in cancer therapy: A review

International Journal of Biological Macromolecules, Год журнала: 2024, Номер 261, С. 129864 - 129864

Опубликована: Янв. 30, 2024

Язык: Английский

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Recent advances in IAP-based PROTACs (SNIPERs) as potential therapeutic agents

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2022, Номер 37(1), С. 1437 - 1453

Опубликована: Май 19, 2022

Proteolytic targeting chimaeras (PROTACs) have been developed as an effective technology for targeted protein degradation. PROTACs are heterobifunctional molecules that can trigger the polyubiquitination of proteins interest (POIs) by recruiting ubiquitin-proteasome system, thereby inhibiting intracellular level POIs. To date, a variety small-molecule (CRBN, VHL, IAP, and MDM2-based PROTACs) developed. IAP-based PROTACs, also known specific nongenetic IAP-dependent erasers (SNIPERs), used to degrade target closely related diseases. Their structures consist three parts, including ligand, E3 ligase linker between them. So far, many SNIPERs extensively studied worldwide performed well in multiple diseases, especially cancer. In this review, we will present most relevant advances field provide our perspective on opportunities challenges become therapeutic agents.

Язык: Английский

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Medicinal Chemistry Strategies for the Development of Bruton’s Tyrosine Kinase Inhibitors against Resistance

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(11), С. 7415 - 7437

Опубликована: Май 20, 2022

Despite significant efficacy, one of the major limitations small-molecule Bruton's tyrosine kinase (BTK) agents is presence clinically acquired resistance, which remains a clinical challenge. This Perspective focuses on medicinal chemistry strategies for development BTK inhibitors against including structure-based design targeting point mutations, e.g., (i) developing noncovalent from covalent inhibitors, (ii) avoiding steric hindrance mutated residues, (iii) making interactions with residue, (iv) modifying solvent-accessible region, and (v) new scaffolds. Additionally, comparative analysis multi-inhibitions presented based cross-comparisons between 2916 unique ligands 283 other kinases that cover 7108 dual/multiple inhibitions. Finally, allosteric site uding proteolysis-targeting chimera (PROTAC) as two potential are addressed briefly, while also illustrating possibilities challenges to find novel BTK.

Язык: Английский

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Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 66(2), С. 1186 - 1209

Опубликована: Дек. 14, 2022

Inducing protein degradation by proteolysis targeting chimeras has gained tremendous momentum as a promising novel therapeutic strategy. Here, we report the design, synthesis, and biological characterization of highly potent chimeric small molecules epigenetic regulator histone deacetylase 8 (HDAC8). We developed effective HDAC8 degraders, exemplified SZUH280 (16e), which effectively induced inhibited cancer cell growth even at low micromolar concentrations. Our preliminary mechanistic studies revealed that hampers DNA damage repair in cells, promoting cellular radiosensitization. In mice, single dose rapid prolonged xenograft tumor tissues. Moreover, alone or combination with irradiation resulted long-lasting regression an A549 mouse model. findings qualify new chemical tool for knockdown may lead to development class therapeutics.

Язык: Английский

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