Therapeutic targeting potential of the protein lysine and arginine methyltransferases to reverse cancer chemoresistance DOI Creative Commons
Isaac Micallef,

Kimberly Fenech,

Byron Baron

et al.

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Dec. 5, 2024

Cancer treatments have continued to improve tremendously over the past decade, but therapy resistance is still a common, major factor encountered by patients diagnosed with cancer. Chemoresistance arises due various circumstances and among these causes, increasing evidence has shown that enzymes referred as protein methyltransferases (PMTs) play significant role in development of chemoresistance cancers. These are responsible for methylation different amino acids, particularly lysine arginine, via (PKMTs) arginine (PRMTs), respectively. Various PMTs been identified be dysregulated cancer chemoresistance. Nonetheless, functional poorly characterised. This advocates need innovative approaches technologies suitable better characterisation their potential clinical inhibitors. In case handful PMTs, inhibitory small molecules which can function anticancer drugs developed also entered trials. Considering all this, become promising valuable target related research. review will give introduction on PKMTs PRMTs families cancers known proteins targeted respective enzymes. The focus then shift towards involved inhibitors against these, together mode action. Lastly, current obstacles future perspectives PMT discussed.

Language: Английский

Epigenetics-targeted drugs: current paradigms and future challenges DOI Creative Commons

Wanlin Dai,

Xinbo Qiao, Yuanyuan Fang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Language: Английский

Citations

25
Biomedical Effects of Protein Arginine Methyltransferase Inhibitors DOI Creative Commons

Mengtong Cao,

Terry Nguyen,

Jiabao Song

et al.

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: 301(3), P. 108201 - 108201

Published: Jan. 16, 2025

Language: Английский

Citations

1
Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1 DOI Creative Commons
Thordur Hendrickson-Rebizant, S Sudhakar, Michael J. Rowley

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(18), P. 15931 - 15946

Published: Sept. 9, 2024

Protein arginine

Language: Английский

Citations

5
Discovery of novel PRMT1 inhibitors: a combined approach using AI classification model and traditional virtual screening DOI Creative Commons

Jungan Zhang,

Yixin Ren,

Yun Teng

et al.

Frontiers in Chemistry, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 20, 2025

Protein arginine methyltransferases (PRMTs) play crucial roles in gene regulation, signal transduction, mRNA splicing, DNA repair, cell differentiation, and embryonic development. Due to its significant impact, PRMTs is a target for the prevention treatment of various diseases. Among PRMT family, PRMT1 most abundant ubiquitously expressed human body. Although extensive research has been conducted on PRMT1, reported inhibitors have not successfully passed clinical trials. In this study, deep learning was employed analyze characteristics existing construct classification model inhibitors. Through molecular docking, series potential were identified. The representative compound (compound 156) demonstrates stable binding protein by hybridization, dynamics simulations, free energy analyses. study discovered novel scaffolds

Language: Английский

Citations

0
PK/PD modeling of targeted protein degraders: Charting new waters and navigating the shallows DOI Creative Commons
Robin Thomas Ulrich Haid, Andreas Reichel

Drug Discovery Today, Journal Year: 2025, Volume and Issue: unknown, P. 104311 - 104311

Published: Feb. 1, 2025

The development of targeted protein degraders has picked up considerable steam recently, with interest stoked further by the first compounds entering Phase III studies. To keep leading biotech start-up firms, big pharma been keen to venture into this new field, bringing along experienced crews drug hunters. At their disposal, they find a burgeoning body literature on pharmacokinetics/pharmacodynamics (PK/PD) models tailor‑made for therapeutic modality. However, ocean opportunities might seem daunting even veteran scientists. Here, we provide orientation and direction researchers approach best suited respective questions.

Language: Английский

Citations

0
Discovery of A First-in-class Protein Arginine Methyltransferase 1 (PRMT1) Degrader for Nonenzymatic Functions Studies DOI
Chao Ma, Hong‐Wei Sun, Chang Shen

et al.

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 291, P. 117625 - 117625

Published: April 14, 2025

Language: Английский

Citations

0
PRMT1‐Mediated SWI/SNF Complex Recruitment via SMARCC1 Drives IGF2BP2 Transcription to Enhance Carboplatin Resistance in Head and Neck Squamous Cell Carcinoma DOI Creative Commons
Shixian Liu, Wentao Zhang, Weiwei Liu

et al.

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

Published: April 24, 2025

Abstract Head and neck squamous cell carcinoma (HNSCC) is a malignancy with poor prognosis chemotherapy resistance. Here, protein arginine methyltransferase 1 (PRMT1) identified as key driver of carboplatin (CBP) resistance in HNSCC. Analyses clinical samples, lines, patient‐derived organoids, xenograft models reveal that PRMT1 promotes tumor growth CBP through novel, methyltransferase‐independent mechanism. Conditional knockout suppresses tumorigenesis enhances sensitivity vivo, highlighting its essential role HNSCC progression. Mechanistically, recruits the SWI/SNF chromatin remodeling complex via direct interaction SMARCC1, leading to transcriptional activation insulin‐like factor 2 mRNA‐binding (IGF2BP2), which growth. Notably, this function independent PRMT1's enzymatic activity, distinguishing it from well‐established roles methylation. Furthermore, pre‐B‐cell leukemia homeobox (PBX2) an upstream activator binds promoter, driving overexpression reinforcing oncogenic network. Clinically, high PBX2, PRMT1, IGF2BP2 expression correlates malignant progression patients. This study uncovers previously unrecognized non‐catalytic highlights PBX2‐PRMT1‐SWI/SNF‐IGF2BP2 axis potential therapeutic target for overcoming

Language: Английский

Citations

0
Overview of PRMT1 Modulators: Inhibitors and Degraders DOI
Jun Wu,

Deping Li,

Li‐Fang Wang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 279, P. 116887 - 116887

Published: Sept. 20, 2024

Language: Английский

Citations

3
Cereblon-recruiting proteolysis targeting chimeras (PROTACs) can determine the selective degradation of HDAC1 over HDAC3 DOI Creative Commons
Aline Renata Pavan, Joshua P. Smalley,

Urvashi Patel

et al.

Chemical Communications, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Cereblon-recruiting PROTACs can degrade HDAC1 with selectivity over HDAC3.

Language: Английский

Citations

0
Therapeutic targeting potential of the protein lysine and arginine methyltransferases to reverse cancer chemoresistance DOI Creative Commons
Isaac Micallef,

Kimberly Fenech,

Byron Baron

et al.

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Dec. 5, 2024

Cancer treatments have continued to improve tremendously over the past decade, but therapy resistance is still a common, major factor encountered by patients diagnosed with cancer. Chemoresistance arises due various circumstances and among these causes, increasing evidence has shown that enzymes referred as protein methyltransferases (PMTs) play significant role in development of chemoresistance cancers. These are responsible for methylation different amino acids, particularly lysine arginine, via (PKMTs) arginine (PRMTs), respectively. Various PMTs been identified be dysregulated cancer chemoresistance. Nonetheless, functional poorly characterised. This advocates need innovative approaches technologies suitable better characterisation their potential clinical inhibitors. In case handful PMTs, inhibitory small molecules which can function anticancer drugs developed also entered trials. Considering all this, become promising valuable target related research. review will give introduction on PKMTs PRMTs families cancers known proteins targeted respective enzymes. The focus then shift towards involved inhibitors against these, together mode action. Lastly, current obstacles future perspectives PMT discussed.

Language: Английский

Citations

0