Highly Specific Cytokine Receptor‐Targeting Chimeras for Targeted Membrane Protein Degradation and Sensitization of Osimertinib in EGFR‐Mutated Non‐Small‐Cell Lung Cancer DOI
Jiawei Wu, Qianqian Gao, Qing Xia

et al.

Advanced Materials, Journal Year: 2025, Volume and Issue: unknown

Published: May 22, 2025

Abstract The ability of cytokine receptors to mediate the internalization targets in lysosomes positions them as specific and effective effectors for protein degradation strategies. However, challenges remain, including potential unintended activation cell‐proliferation‐related receptors, well limitations programmability structural flexibility degradators. In this work, a CXCR7‐targeting chimera (AP‐CRTAC) that functions CXCR7 inducer by covalently linking membrane protein‐targeting aptamer with mutant‐CXCL12 mimic peptide is developed. This selectively binds without activating CXCR4. AP‐CRTAC, which incorporates various forms from DNA, RNA, or even bispecific aptamers, has shown significant efficacy degrading one more proteins mutants on cell surface. Moreover, AP‐CRTAC constructed 2′ F‐pyrimidine‐modified RNA targeting EGFR effectively degrades mutations. Notably, enhances sensitivity L858R/T790M/C797S triple mutant lung cancer cells, are resistant current EGFR‐targeted therapies, third‐generation inhibitor osimertinib both vitro vivo settings. research introduces an engineered high specificity targeted surface proteins, while minimizing unwanted side effects.

Language: Английский

PROTACs coupled with oligonucleotides to tackle the undruggable DOI
Guangshuai Zhang,

Si Yan,

Yan Liu

et al.

Bioanalysis, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: Feb. 3, 2025

Undruggable targets account for roughly 85% of human disease-related and represent a category therapeutic that are difficult to tackle with traditional methods, but their considerable clinical importance. These generally defined by planar functional interfaces the absence efficient ligand-binding pockets, making them unattainable conventional pharmaceutical strategies. The advent oligonucleotide-based proteolysis-targeting chimeras (PROTACs) has instilled renewed optimism in addressing these challenges. PROTACs facilitate targeted degradation undruggable entities, including transcription factors (TFs) RNA-binding proteins (RBPs), via proteasome-dependent mechanisms, thereby presenting novel approaches diseases linked targets. This review offers an in-depth examination recent progress integration PROTAC technology oligonucleotides target traditionally proteins, emphasizing design principles mechanisms action innovative PROTACs.

Language: Английский

Citations

2
Rational Design of Dual Degraders by Incorporating Molecular Glue Structural Features into PROTAC Degraders DOI
Bowen Zhang, Shan Gao,

Ting-Ting Wu

et al.

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

Published: May 9, 2025

PROTAC and molecular glue present a novel therapeutic approach to tackle diseases propelled by the aberrant expression of disease-causing proteins. In this study, we identified number AR/AR-V7 GSPT1 degraders that possess both characteristics. The exploration SAR led discovery BWA-6047 as potent degrader. exhibited protein degradation in 22Rv1 cells (AR: DC50 = 3.7 nM, Dmax 90%; AR-V7: 3.0 93%; GSPT1: 1.2 94%). Mechanism experiments indicate functions degrade target Oral administration at 20 mpk significantly inhibited LNCaP xenograft tumor growth mice without obvious toxicity. Dual represent class promising mechanism compounds for further extensive evaluations prostate cancer treatment.

Language: Английский

Citations

1
Identifying Semaphorin 3C as a Biomarker for Sarcopenia and Coronary Artery Disease Via Bioinformatics and Machine Learning DOI
Ran Shu, Zhuoqi Li,

Xitong Lin

et al.

Archives of Gerontology and Geriatrics, Journal Year: 2025, Volume and Issue: 131, P. 105762 - 105762

Published: Jan. 15, 2025

Language: Английский

Citations

0
Identification of actionable targeted protein degradation effector sites through Site-specific Ligand Incorporation-induced Proximity (SLIP) DOI Creative Commons
Zhangping Xiao,

Efthymios Spyridon Gavriil,

Fangyuan Cao

et al.

Published: Feb. 4, 2025

ABSTRACT Targeted protein degradation (TPD) is a rapidly emerging and potentially transformative therapeutic modality. However, the large majority of >600 known ubiquitin ligases have yet to be exploited as TPD effectors by proteolysis-targeting chimeras (PROTACs) or molecular glue degraders (MGDs). We report here chemical–genetic platform, Site-specific Ligand Incorporation-induced Proximity (SLIP), identify actionable (“PROTACable”) sites on any potential effector in intact cells. SLIP uses genetic code expansion (GCE) encode copper-free “click” ligation at specific site cells, enabling situ formation covalent PROTAC-effector conjugate against target interest (POI). Modification drives targeted protein, establishing these for TPD. Using SLIP, we systematically screened dozens across E3 E2 enzymes from diverse classes, identifying multiple novel PROTACable which are competent adds powerful approach proximity-induced pharmacology (PIP) toolbox, future ligand discovery fully enable TPD, other PIP modalities.

Language: Английский

Citations

0
Design, Synthesis, and Biological Evaluation of Novel BTK-targeting Proteolysis Targeting Chimeras (PROTACs) with Enhanced Pharmacokinetic Properties DOI
Ying‐Hung Lin, Jing Liu, Xiaohe Tian

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117420 - 117420

Published: Feb. 22, 2025

Language: Английский

Citations

0
PSPC1 bridges cancer stemness and malignancy in acute myeloid leukemia DOI

Hsi-Wen Yeh,

Yaw‐Dong Lang, Hsin‐Yi Lee

et al.

Cell stem cell, Journal Year: 2025, Volume and Issue: 32(3), P. 335 - 337

Published: March 1, 2025

Language: Английский

Citations

0
The Endo-GeneScreen Platform Identifies Drug-Like Probes that Regulate Endogenous Protein Levels within Physiological Contexts DOI Open Access

Preston Samowitz,

László Radnai, Thomas Vaissière

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

Traditional phenotypic drug discovery platforms have suffered from poor scalability and a lack of mechanistic understanding newly discovered probes. To address this, we created Endo- GeneScreen (EGS), high-throughput enabled screening platform that identifies bioactive small molecules capable regulating endogenous protein expression encoded by any preselected target gene within biologically appropriate context. As proof-of-concept, EGS successfully identified candidates up-regulate neuronal Syngap1, causes neurodevelopmental disorder when haploinsufficient. For example, SR-1815, previously unknown undescribed kinase inhibitor, alleviated major cellular consequences Syngap1 loss-of-function restoring normal SynGAP levels dampening hyperactivity haploinsufficient neurons. Moreover, demonstrate assays accelerate preclinical development facilitate mode-of-action deconvolution studies. Thus, first-in-class molecule probes promote biological precision therapeutic development.

Language: Английский

Citations

0
Design and Synthesis of a Clickable Cell-Permeable Pseudopeptide Pin1 Inhibitor with Antiproliferative Effects on Human Multiple Myeloma Cell Line DOI

Lorenzo Meneghelli,

Stephanie Davidson,

Anthony Gineste

et al.

Chemical Communications, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

The synthesis of a library minimal-backbone, cell-permeable, clickable pseudopeptide Pin1 ligands with potential applications in drug development and biochemical studies is reported. ligands' affinity constants were evaluated using NMR. lead compound 4b, demonstrated effective cell permeability, inhibitory activity, an antiproliferative effect on multiple myeloma line.

Language: Английский

Citations

0
Potential Benefits of In Silico Methods: A Promising Alternative in Natural Compound’s Drug Discovery and Repurposing for HBV Therapy DOI Creative Commons
Samuel Chima Ugbaja, Aganze Gloire-Aimé Mushebenge, Hezekiel M. Kumalo

et al.

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(3), P. 419 - 419

Published: March 16, 2025

Hepatitis B virus (HBV) is an important global public health issue. The World Health Organization (WHO) 2024 Global Report estimated that the prevalence of people living with HBV infection 254 million, incidence 1.2 million new infections yearly. Previous studies have shown natural compounds antiviral inhibition potentials. In silico methods such as molecular docking, virtual screening, pharmacophore modeling, quantitative structure–activity relationship (QSAR), and dynamic simulations been successfully applied in identifying bioactive strong binding energies treatment targets. COVID-19 pandemic necessitated importance repurposing already approved drugs using methods. This study aimed at unveiling benefits techniques a potential alternative compounds’ drug discovery for therapy. Relevant articles from PubMed, Google Scholar, Web Science were retrieved analyzed. Furthermore, this comprehensively reviewed literature containing identified essential proteins. Notably, hesperidin, quercetin, kaempferol, myricetin, flavonoids hepatitis surface antigen (HBsAg). investigation reveals offer understanding mechanisms action, reveal previously overlooked viral targets (including PreS1 Domain HBsAg cccDNA (Covalently Closed Circular DNA) regulators, facilitate creation specific inhibitors. integration silico, vitro, vivo insights further highlight Moreover, combination compounds, approach, improves chances personalized precision medicine treatment. Therefore, we recommend strategies combine vivo, approaches to effective drugs.

Language: Английский

Citations

0
E3 ubiquitin ligases and their therapeutic potential in disease Management DOI
Geet Madhukar, Md Azizul Haque, Shawez Khan

et al.

Biochemical Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 116875 - 116875

Published: March 1, 2025

Language: Английский

Citations

0