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

Rational design of phytovirucide inhibiting nucleocapsid protein aggregation in tomato spotted wilt virus DOI Creative Commons
Ningning Zan, Jiao Li, Jiahui Yao

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 27, 2025

Ineffectiveness of managing plant viruses by chemicals has posed serious challenges in crop production. Recently, phase separation shown to play a key role viral lifecycle. Using inhibitors that can disturb biomolecular condensates formed for virus control been reported medical field. However, the applicability this promising antiviral tactic protection not explored. Here, we report an inhibitor, Z9, targets tomato spotted wilt (TSWV) N protein. Z9 is capable interacting with amino acids nucleic acid binding region TSWV N, disrupting assembly and RNA into phase-separated condensates, reduction which detrimental stability This study provides strategy separation-based control. Biomolecular have recognized as crucial process life cycle. authors inhibitor targeting nucleocapsid protein (N) disrupt its potential

Language: Английский

Citations

1
Advancements in delivery Systems for Proteolysis-Targeting Chimeras (PROTACs): Overcoming challenges and expanding biomedical applications DOI

Yawei Yu,

Weitong Hu,

Yihua Xu

et al.

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: unknown, P. 113719 - 113719

Published: April 1, 2025

Language: Английский

Citations

0
KLF12 Aggravates Angiotensin II‐Induced Cardiac Remodeling in Male Mice by Transcriptionally Inhibiting SMAD7 DOI Creative Commons
Min Hu, Shi‐Yu Huang, Ying Gao

et al.

Journal of the American Heart Association, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Background Adverse left ventricular remodeling and subsequent heart failure remain a major cause of patient morbidity mortality worldwide. The KLF family transcription factors plays crucial roles in injury. KLF12 (Krüppel‐like factor 12) is that regulates multiple disease processes, although the specific role cardiac remains unclear. Methods Results In our study, we observed significant upregulation expression hearts. increased primarily originated from fibroblasts during fibrotic response induced by angiotensin II. To investigate effects KLF12, performed RNA‐seq found overexpression significantly upregulated associated pathway. Hence, generated adult mice with fibroblast‐specific using lentivirus or miRNA (miR‐1/133TS) technology. Compared control mice, KLF12‐miR1/133TS transfected exhibited exacerbated function. Mechanistically, discovered directly binds to promoter Smad7, leading activation TGF‐β (transforming growth beta)‐Smad3 Conclusions conclusion, promoted development II‐induced male mice. Targeting may be promising therapeutic approach treat remodeling.

Language: Английский

Citations

0
Virus-inspired biogenic delivery system for advancing cancer therapy DOI Creative Commons
Di Sun, Liang Hao,

Qianwen Mu

et al.

Biomedical Technology, Journal Year: 2025, Volume and Issue: 9, P. 100069 - 100069

Published: Feb. 8, 2025

Language: Английский

Citations

0
A Dual-Targeted Molecule for Disease-Activatable Proteolysis Targeting Chimeras and Targeted Radionuclide Therapy of Cancer DOI
Yuan Zhang, Wei Gu,

Chen Wan

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7897 - 7907

Published: Feb. 24, 2025

Proteolysis targeting chimeras (PROTACs) represent a cutting-edge approach for targeted protein degradation in cancer therapy, yet they face challenges such as poor pharmacokinetics and specificity issues, leading to undesirable off-target effects limited antitumor potency. To address these we introduce dual-targeted unimolecular theranostic probes (e.g., radioactive 177Lu-P-A its cold counterpart natLu-P-A) disease-activatable PROTACs combination with radionuclide therapy (TRT) against prostate high effectiveness. The achieve cathepsin B (CTSB)-activatable pro-PROTAC moiety precise of bromodomain-containing 4 (BRD4) prostate-specific membrane antigen (PSMA)-targeted 177Lu-based TRT. Owing the favorable PSMA-mediated excellent efficiency, probe possesses tumor imaging accumulation capacity therapeutic units highly effective In contrast, free unit ARV-771) shows no observable effect due ability. Importantly, BRD4 proteolysis by PROTAC activation can downregulate radiosensitivity-associated RAD51AP1 expression, synergistically enhancing TRT promoting apoptosis after combined compared individual treatment regimes. Additionally, demonstrates renal clearance, underscoring biosafety potential clinical translation. This study presents therapy.

Language: Английский

Citations

0
Sorghum Grain-Derived Kafirin Nanoparticles For Effective Delivery of Corosolic Acid into Breast Cancer Cells for Potential Treatment of Breast Cancer DOI

Priya Petchimuthu,

Selvaraj Kunjiappan, Sureshbabu Ram Kumar Pandian

et al.

Journal of Cluster Science, Journal Year: 2025, Volume and Issue: 36(3)

Published: April 4, 2025

Language: Английский

Citations

0
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

0