Recent advancements in targeted protein knockdown technologies—emerging paradigms for targeted therapy DOI Creative Commons
Mansi Joshi, Pranay Dey, Abhijit De

et al.

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2023, Volume and Issue: 4(6), P. 1227 - 1248

Published: Dec. 26, 2023

A generalized therapeutic strategy for various disease conditions, including cancer, is to deplete or inactivate harmful protein targets. Various forms of gene silencing molecules, e.g., small molecule inhibitors, RNA interference (RNAi), and microRNAs (miRNAs) have been used against druggable Over the past few years, targeted degradation (TPD) approaches developed direct candidate proteins. Among TPD approaches, proteolysis targeting chimeras (PROTACs) emerged as one most promising selective elimination proteins via ubiquitin-proteasome system. Other than PROTACs, methods with potential use include intrabody-mediated knockdown tripartite motif-21 (TRIM-21) mediated TRIM-Away. In this review, their modes action, advantages over conventional are summarized. cancers, disease-associated functions often executed by specific post-translational modifications (PTMs). The role TRIM-Away highlighted in PTM target Moreover, application challenges prospective clinical diseases also discussed.

Language: Английский

Targeting intracellular cancer proteins with tumor‐microenvironment‐responsive bispecific nanobody‐PROTACs for enhanced therapeutic efficacy DOI Creative Commons
Changping Deng, Jiacheng Ma, Yuping Liu

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(2)

Published: Jan. 19, 2025

Abstract Proteolysis targeting chimeras (PROTACs) are pivotal in cancer therapy for their ability to degrade specific proteins. However, non‐specificity can lead systemic toxicity due protein degradation normal cells. To address this, we have integrated a nanobody into the PROTACs framework and leveraged tumor microenvironment enhance drug specificity. In this study, engineered BumPeD, novel bispecific nanobody‐targeted PROTACs‐like platform, by fusing two nanobodies with Furin protease cleavage site (RVRR) degron sequence (ALAPYIP or KIGLGRQKPPKATK), enabling direct of intracellular We utilized KN035 Nb4A target PD‐L1 (programmed death ligand 1) on cell surface Survivin, respectively. vitro experiments showed that BumPeD triggers Survivin via ubiquitin‐proteasome pathway, inducing apoptosis suppressing bladder proliferation migration. vivo further confirmed BumPeD's robust anti‐tumor efficacy, underscoring its potential as precise strategy therapy. Our platform provides systematic approach developing effective practical degraders, offering targeted theoretical basis experimental support development degradative drugs, well new directions

Language: Английский

Citations

2
PROTACs: A novel strategy for cancer drug discovery and development DOI Creative Commons
Xin Han, Yi Sun

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 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.

Language: Английский

Citations

24
Recent Advances on Targeting Proteases for Antiviral Development DOI Creative Commons
Pedro Henrique Oliveira Borges, Sabrina Baptista Ferreira, Floriano Paes Silva

et al.

Viruses, Journal Year: 2024, Volume and Issue: 16(3), P. 366 - 366

Published: Feb. 27, 2024

Viral proteases are an important target for drug development, since they can modulate vital pathways in viral replication, maturation, assembly and cell entry. With the (re)appearance of several new viruses responsible causing diseases humans, like West Nile virus (WNV) recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), understanding mechanisms behind blocking protease’s function is pivotal development antiviral drugs therapeutical strategies. Apart from directly inhibiting protease, usually by targeting its active site, have been explored to impair activity, such as inducing protein aggregation, allosteric sites or degradation cellular proteasomes, which be extremely valuable when considering emerging drug-resistant strains. In this review, we aim discuss advances on a broad range inhibitors, therapies molecular approaches inactivation degradation, giving insight different possible strategies against class target.

Language: Английский

Citations

9
Clozapine as an E3 Ligand for PROTAC Technology DOI

Reina Takano,

Nobumichi Ohoka, Takashi Kurohara

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: 16(2), P. 258 - 262

Published: Jan. 8, 2025

New ubiquitin ligase (E3) ligands are crucial for developing proteolysis-targeting chimeras (PROTACs) to induce the degradation of a target protein. In this study, we developed PROTAC using antipsychotic drug clozapine as new E3 ligand. First, targeting model HaloTag protein (Halo-PEG-Clozapine) was synthesized, and induced HaloTag-fused in cell culture system. Another cancer therapeutic estrogen receptor α (ERα) (Tamoxifen-PEG-Clozapine) synthesized ERα MCF-7 breast cells. Experiments with inhibitors siRNAs showed that Tamoxifen-PEG-Clozapine degraded via ubiquitin-proteasome system uses component N-recognin 5. These results indicate is promising ligand may expand molecular design PROTACs, contributing advancement discovery by facilitating disease-related proteins.

Language: Английский

Citations

0
Synthesis of α-(azidomethyl)glutarimide and its applicationin construction of potential Cereblon ligands <em>via</em> the CuAAC reaction DOI

Liliya R Khuzhakhmetova,

Anna Alekseevna Ananeva,

Grigory Kantin

et al.

Mendeleev Communications, Journal Year: 2025, Volume and Issue: 35(1), P. 69 - 72

Published: Jan. 1, 2025

Language: Английский

Citations

0
Novel Small Molecule DZ-865B Effectively Degrades BCL6, Promotes Apoptosis and Reduces Proliferation of Diffuse Large B-Cell Lymphoma Cells DOI Creative Commons
Yanfeng Wang,

Beier Jiang,

Yichen Yin

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Abstract B-cell lymphoma 6 (BCL6) is a transcriptional repressor essential for B lymphocyte differentiation and germinal center formation through its BTB structural domain. Overexpression of BCL6 strongly implicated in the progression diffuse large (DLBCL), making it promising therapeutic target. This study aims to identify novel small molecule, synthesized via proteolysis-targeting chimeras (PROTACs), capable degrading BCL6, thereby inhibiting DLBCL growth providing foundation future preclinical studies. The expression was analyzed using Cancer Genome Atlas (TCGA) database Human Protein Atlas. Western blotting assays confirmed tumor cell lines, leading identification molecule compound DZ-865B. To evaluate DZ-865B’s vitro efficacy, multiple were performed, including protein immunoblotting, immunofluorescence, quantitative PCR, EDU proliferation, soft agar cloning assays. TCGA analysis revealed significant overexpression (P < 0.05), corroborated by immunohistological staining western blotting. DZ-865B induced degradation lines (OCI-LY-1 SU-DHL-4) concentration- time-dependent manner, reducing nuclear levels. Notably, did not alter mRNA levels but modulated downstream gene expression, activation apoptosis pathway proteins inhibition DNA synthesis, effectively suppressing growth. demonstrates that targets degrades cells, promoting cellular proliferation. These findings highlight as potential agent lymphoma.

Language: Английский

Citations

0
Catalytic Castagnoli--Cushman reaction-based synthesis of tetrahydroisoquinolone--glutarimide dyads and their evaluation as potential cereblon ligands DOI

Anna Alekseevna Ananeva,

Grigory Kantin, Dmitry Dar’in

et al.

Mendeleev Communications, Journal Year: 2025, Volume and Issue: 35(3), P. 285 - 288

Published: Jan. 1, 2025

Language: Английский

Citations

0
Recent insights of PROTAC developments in inflammation-mediated and autoimmune targets: a critical review DOI

Mary Sravani Galla,

Nitika Sharma, Priyanka Mishra

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 15(8), P. 2585 - 2600

Published: Jan. 1, 2024

A comprehensive outlook of PROTAC breakthroughs in targeting anti-inflammatory and auto-immune diseases as promising therapeutic approaches for various unresolved disorders.

Language: Английский

Citations

4
PROTAC Beyond Cancer- Exploring the New Therapeutic Potential o f Proteolysis Targeting Chimeras DOI
Ritesh Bhole,

S. Patil,

Harshad S. Kapare

et al.

Current Topics in Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 24(23), P. 2050 - 2073

Published: July 4, 2024

In the realm of oncology, transformative impact PROTAC (PROteolysis TAgeting Chimeras) technology has been particularly pronounced since its introduction in 21st century. Initially conceived for cancer treatment, PROTACs have evolved beyond their primary scope, attracting increasing interest addressing a diverse array medical conditions. This expanded focus includes not only oncological disorders but also viral infections, bacterial ailments, immune dysregulation, neurodegenerative conditions, and metabolic disorders. comprehensive review explores broadening landscape application, highlighting ongoing developments innovations aimed at deploying these molecules across spectrum diseases. Careful consideration design challenges associated with reveals that, when appropriately addressed, compounds present significant advantages over traditional therapeutic approaches, positioning them as promising alternatives. To evaluate efficacy molecules, assays is employed, ranging from High-Throughput Imaging (HTI) to Cell Painting assays, CRBN engagement Fluorescence Polarization amplified luminescent proximity homogeneous Timeresolved fluorescence energy transfer Isothermal Titration Calorimetry assays. These assessments collectively contribute nuanced understanding performance. Looking ahead, trajectory suggests potential recognition versatile strategy an expansive range Ongoing progress this field sets stage emerge valuable tools multifaceted treatments.

Language: Английский

Citations

2
Discovery of ERD-1233 as a Potent and Orally Efficacious Estrogen Receptor PROTAC Degrader for the Treatment of ER+ Human Breast Cancer DOI
Ranjan Kumar Acharyya, Rohan Kalyan Rej, Biao Hu

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 19010 - 19037

Published: Nov. 1, 2024

Despite the development of highly effective therapies for treatment estrogen receptor α (ERα)-positive human breast cancer, clinical resistance to current requires novel therapeutic strategies. Herein, we report discovery ERD-1233 as a potent and orally efficacious ERα degrader designed using PROTAC technology. was developed based on Lasofoxifene ER binding moiety cereblon ligand through extensive optimization linker. potently effectively reduces protein in vitro achieves excellent oral bioavailability mice rats. Oral administration ER+ tumors tumor regression wild-type MCF-7 xenograft model strong growth inhibition ESR1Y537S mutated mice. Our data demonstrate that is promising evaluation new therapy cancer.

Language: Английский

Citations

2