Cited by Drug discovery targeting protein arginine methyltransferase 5 (PRMT5): an update

Discovery of a Potent and Selective Protein Arginine Methyltransferase 5 (PRMT5) PROTAC Degrader DOI

Yue Zhong,

Huensuk Kim,

Chao Qian

et al.

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

Published: April 15, 2025

Protein arginine methyltransferase 5 (PRMT5) plays crucial roles in the regulation of various biological processes through mono- and symmetric dimethylation protein substrates. PRMT5 is overexpressed human cancers its overexpression associated with poor prognosis. We previously reported first-in-class degrader, MS4322, which also only von Hippel-Lindau (VHL)-recruiting degrader to date. Here, we performed structure-activity relationship (SAR) studies exploring linkers ligands VHL PRMT5, resulted best-in-class MS115 (compound 10). Compound 10 potently selectively degraded coactivator, MEP50, concentration-, time-, ubiquitin-proteasome system-dependent manners. It displayed much improved PRMT5/MEP50 degradation potency over translated better antiproliferative effect both breast prostate cancer cells. Overall, discovered a highly potent selective complex an invaluable chemical biology tool potential therapeutic.

Language: Английский

Citations

PRMT1-Catalyzed NUSAP1 Methylation Enhances Notch2 Signaling and 5-FU Resistance in Gastric Cancer DOI

Feng Wang,

Steve Jiang,

Guoli Li

et al.

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

Published: Feb. 3, 2025

Abstract 5-Fluorouracil (5-FU) resistance remains a significant challenge in the treatment of gastric cancer, limiting its clinical efficacy. Our study identifies NUSAP1, nucleolar and spindle-associated protein, as key driver 5-FU cancer. Proteomic analyses 5-FU-resistant cancer cell lines revealed that NUSAP1 is significantly upregulated, functional studies demonstrated essential role promoting resistance, proliferation, migration, invasion, tumor growth. Mechanistic investigations undergoes asymmetric dimethylation (ADMA) at R418 R422, mediated by PRMT1, with R422 site being critical for function. interacts PEST domain Notch2 through site, inhibiting ubiquitination stabilizing expression, thereby activating signaling pathway. This pathway closely linked to progression chemoresistance. Inhibition PRMT1 or mutation abrogated NUSAP1’s ability stabilize regulate downstream signaling. These findings unveil novel mechanism which promotes highlight therapeutic potential targeting NUSAP1-Notch2 axis overcoming

Language: Английский

Citations

Unlocking the power of imidazoquinolines: recent advances in anticancer and immunotherapeutic strategies DOI

Ranjini Jenifer R,

Badruzzaman Choudhury,

Mohammed Mujahid Alam

et al.

Future Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 17

Published: April 15, 2025

The challenges in drug discovery aiming to mitigate cancer progression are the thrust area of scientific research for several decades. Since advent heterocyclic chemistry, programs have made significant achievements that lead development numerous drugs with broad spectrum potencies, contributing both diagnostic and therapeutic advancements. Till date, efforts discover more potent efficient candidates underway minimize adverse side effects existing chemotherapeutics. In view above, small-molecule agonists can interact different immune modulators like toll receptor-7 (TLR-7) TLR-8 being investigated explored. These expected display profound effect on anti-tumoral activity by enhancing production proinflammatory cytokines. Recently, imidazoquinoline derivatives proven TLR agonist activities emerged as promising anticancer therapeutics. With advancements technology evolution new scopes discovery, strategies adopted, particularly help nanotechnology, immune-technology, combination etc., curb various types cancers. Herein, novel therapeutics imidazoquinolines reported last 5 years, their structure-activity relationship along important synthetic schemes agonists, discussed.

Language: Английский

Citations

PRMT1-catalyzed NUSAP1 methylation enhances Notch2 signaling and 5-FU resistance in gastric cancer DOI

Steve Jiang,

Guoli Li,

Shihan Peng

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: May 20, 2025

Language: Английский

Citations

Advancing target validation with PROTAC technology DOI

Margaret Spitz,

Aseel Kashkush,

Raphael I. Benhamou

et al.

Expert Opinion on Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: April 5, 2025

Targeted protein degradation (TPD) is a cutting-edge technology that provides new avenues for drug discovery and development. PROteolysis TArgeting Chimeras (PROTACs) are the most established advanced TPD strategy, enabling selective of disease-associated 'undruggable' proteins interest (POIs) by leveraging cell's natural machinery. To confirm PROTAC-induced proximity drives degradation, target validation ternary complex formation must be thoroughly assessed. In this perspective, authors detail some widely used in silico, structural, vitro, cellulo methods to validate PROTAC engagement formation. Additionally, they discuss growing use PROTACs as chemical probes novel identification validation. Target essential approach, ongoing studies should prioritize confirming using assays conducted under physiologically relevant cellular conditions. The believe proteomics analyses among valuable tools elucidating mechanism, selectivity, outcomes PROTACs. They also remain optimistic about future development their engagement. While rapidly advancing, it still holds vast opportunities exploration, offering significant potential further both biological research drive drugs.

Language: Английский

Citations

Drug discovery targeting protein arginine methyltransferase 5 (PRMT5): an update DOI

Zhouyang Gu, Weijia Kong, Xing Liu

et al.

Bioorganic & Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 128, P. 118240 - 118240

Published: May 20, 2025

Language: Английский

Citations