Targeting Arginine Methyltransferase PRMT5 for Cancer Therapy: Updated Progress and Novel Strategies

An updated patent review of protein arginine N-methyltransferase inhibitors (2019–2022)

(2023) Jinyun Dong et al.   EXPERT OPINION ON THERAPEUTIC PATENTS

Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers

(2022) Christopher R. Smith et al.   JOURNAL OF MEDICINAL CHEMISTRY

PROTAC targeted protein degraders: the past is prologue

(2022) Miklós Békés et al.   NATURE REVIEWS DRUG DISCOVERY

Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance

(2022) Zuqin Wang et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structure-Aided Design, Synthesis, and Biological Evaluation of Potent and Selective Non-Nucleoside Inhibitors Targeting Protein Arginine Methyltransferase 5

(2022) Deqin Rong et al.   JOURNAL OF MEDICINAL CHEMISTRY

Design and synthesis of unprecedented 9- and 10-membered cyclonucleosides with PRMT5 inhibitory activity

(2022) Shuhei Kawamura et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Discovery of the First-in-Class G9a/GLP Covalent Inhibitors

(2022) Kwang-Su Park et al.   JOURNAL OF MEDICINAL CHEMISTRY

Tricyclic Carboxamide Derivatives as PRMT5 Inhibitors for Treating Cancer

(2022) Ram W. Sabnis   ACS Medicinal Chemistry Letters

PRMT5 activates AKT via methylation to promote tumor metastasis

(2022) Lei Huang et al.   Nature Communications

Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors in Oncology Clinical Trials: A review

(2022) Kavanya Feustel et al.   Journal of Immunotherapy and Precision Oncology

Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitors

(2022) Christopher R. Smith et al.   BIOORGANIC & MEDICINAL CHEMISTRY

Atropisomeric Racemization Kinetics of MRTX1719 Using Chiral Solvating Agent-Assisted 19F NMR Spectroscopy

(2022) Svitlana Kulyk et al.   ACS Omega

Medicinal chemistry strategies targeting PRMT5 for cancer therapy

(2022) Siyu Fu et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy

(2022) Ming-Shu Wang et al.   Journal of Medicinal Chemistry

Discovery of the Potent and Highly Selective PARP7 Inhibitor as a Novel Immunotherapeutic Agent for Tumors

(2022) Hongfeng Gu et al.   Journal of Medicinal Chemistry

Discovery of D6808, a Highly Selective and Potent Macrocyclic c-Met Inhibitor for Gastric Cancer Harboring MET Gene Alteration Treatment

(2022) Chaofan Wang et al.   Journal of Medicinal Chemistry

Development of Macrocyclic PRMT5–Adaptor Protein Interaction Inhibitors

(2022) Adrian Krzyzanowski et al.   Journal of Medicinal Chemistry

Protein Arginine Methyltransferases as Therapeutic Targets in Hematological Malignancies

(2022) Camille Sauter et al.   Cancers

CARM1/PRMT4: Making Its Mark beyond Its Function as a Transcriptional Coactivator

(2021) Samyuktha Suresh et al.   TRENDS IN CELL BIOLOGY

Protein arginine methyltransferase 5: a potential cancer therapeutic target

(2021) Yuanyang Yuan et al.   CELLULAR ONCOLOGY

Biochemical Investigation of the Interaction of pICln, RioK1 and COPR5 with the PRMT5‐MEP50 Complex

(2021) Herbert Waldmann et al.   CHEMBIOCHEM

Targeting Epigenetic Regulators with Covalent Small-Molecule Inhibitors

(2021) Yi Zhang et al.   JOURNAL OF MEDICINAL CHEMISTRY

PRMT5: a putative oncogene and therapeutic target in prostate cancer

(2021) Elena Beketova et al.   CANCER GENE THERAPY

The Discovery of Two Novel Classes of 5,5-Bicyclic Nucleoside-Derived PRMT5 Inhibitors for the Treatment of Cancer

(2021) Ryan V. Quiroz et al.   JOURNAL OF MEDICINAL CHEMISTRY

Development of a Flexible and Robust Synthesis of Tetrahydrofuro[3,4-b]furan Nucleoside Analogues

(2021) David A. Candito et al.   JOURNAL OF ORGANIC CHEMISTRY

Protein arginine methylation: from enigmatic functions to therapeutic targeting

(2021) Qin Wu et al.   NATURE REVIEWS DRUG DISCOVERY

Profiling PRMT methylome reveals roles of hnRNPA1 arginine methylation in RNA splicing and cell growth

(2021) Wen-juan Li et al.   Nature Communications

PF-06939999, a potent and selective PRMT5 inhibitor, in patients with advanced or metastatic solid tumors: A phase 1 dose escalation study.

(2021) Jordi Rodon Ahnert et al.   JOURNAL OF CLINICAL ONCOLOGY

Discovery of a First-in-Class Inhibitor of the PRMT5–Substrate Adaptor Interaction

(2021) David C. McKinney et al.   JOURNAL OF MEDICINAL CHEMISTRY

Molecular basis for substrate recruitment to the PRMT5 methylosome

(2021) Kathleen M. Mulvaney et al.   MOLECULAR CELL

Prmt5 promotes vascular morphogenesis independently of its methyltransferase activity

(2021) Aurélie Quillien et al.   PLoS Genetics

Structure, Activity and Function of the Protein Arginine Methyltransferase 6

(2021) Somlee Gupta et al.   Life-Basel

Structure and Function of Protein Arginine Methyltransferase PRMT7

(2021) Levon Halabelian et al.   Life-Basel

Targeting protein arginine methyltransferase 5 in cancers: Roles, inhibitors and mechanisms

(2021) Yingqing Chen et al.   BIOMEDICINE & PHARMACOTHERAPY

Protein arginine N-methyltransferase 5 in colorectal carcinoma: Insights into mechanisms of pathogenesis and therapeutic strategies

(2021) Wafaa Abumustafa et al.   BIOMEDICINE & PHARMACOTHERAPY

Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes

(2021) Tamanna Haque et al.   BLOOD

Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

(2021) Jigang Fan et al.   JOURNAL OF MEDICINAL CHEMISTRY

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance

(2021) Kristen Jensen-Pergakes et al.   MOLECULAR CANCER THERAPEUTICS

Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity

(2021) Dirk Brehmer et al.   MOLECULAR CANCER THERAPEUTICS

Novel PRMT5 Inhibitors for Treating Cancer

(2021) Ram W. Sabnis   ACS Medicinal Chemistry Letters

PRMT5: An Emerging Target for Pancreatic Adenocarcinoma

(2021) Michael K. C. Lee et al.   Cancers

Structure, Activity, and Function of PRMT1

(2021) Charlène Thiebaut et al.   Life-Basel

Structure, Activity and Function of the PRMT2 Protein Arginine Methyltransferase

(2021) Vincent Cura et al.   Life-Basel

The Structure and Functions of PRMT5 in Human Diseases

(2021) Aishat Motolani et al.   Life-Basel

High PRMT5 expression is associated with poor overall survival and tumor progression in bladder cancer

(2020) Lei Tan et al.   Aging-US

Regulation of a PRMT5/NF-κB Axis by Phosphorylation of PRMT5 at Serine 15 in Colorectal Cancer

(2020) Antja-Voy Hartley et al.   INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

Discovery of M-808 as a Highly Potent, Covalent, Small-Molecule Inhibitor of the Menin–MLL Interaction with Strong In Vivo Antitumor Activity

(2020) Shilin Xu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Discovery of a First-in-Class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor

(2020) Yudao Shen et al.   JOURNAL OF MEDICINAL CHEMISTRY

Modulating the modulators: regulation of protein arginine methyltransferases by post-translational modifications

(2020) Antja-Voy Hartley et al.   DRUG DISCOVERY TODAY

Discovery of First-in-class Protein Arginine Methyltransferase 5 (PRMT5) Degraders

(2020) Yudao Shen et al.   JOURNAL OF MEDICINAL CHEMISTRY

PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity

(2020) Hyungsoo Kim et al.   Science Translational Medicine

PRMT5 promotes cancer cell migration and invasion through the E2F pathway

(2020) Wojciech Barczak et al.   Cell Death & Disease

Allosteric Modulation of Protein Arginine Methyltransferase 5 (PRMT5)

(2020) Rachel L. Palte et al.   ACS Medicinal Chemistry Letters

537MO First-in-human study of JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, in patients with advanced cancers

(2020) M. Vieito Villar et al.   ANNALS OF ONCOLOGY

Methylation of the central transcriptional regulator KLF4 by PRMT5 is required for DNA end resection and recombination

(2020) Cintia Checa-Rodríguez et al.   DNA REPAIR

Protein Arginine Methyltransferase PRMT5 Regulates Fatty Acid Metabolism and Lipid Droplet Biogenesis in White Adipose Tissues

(2020) Zhihao Jia et al.   Advanced Science

A patent review of arginine methyltransferase inhibitors (2010-2018)

(2019) Xiao Li et al.   EXPERT OPINION ON THERAPEUTIC PATENTS

Allosteric Modulator Discovery: From Serendipity to Structure-Based Design

(2019) Shaoyong Lu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Protein Arginine Methyltransferase 5 (PRMT5) Promotes Survival of Lymphoma Cells via Activation of WNT/β-CATENIN and AKT/GSK3β Proliferative Signaling

(2019) Jihyun Chung et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Nucleoside Protein Arginine Methyltransferase 5 (PRMT5) Inhibitors

(2019) Hong Lin et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

Covalent Inhibitors of Protein–Protein Interactions Targeting Lysine, Tyrosine, or Histidine Residues

(2019) Luca Gambini et al.   JOURNAL OF MEDICINAL CHEMISTRY

Proteomics profiling of arginine methylation defines PRMT5 substrate specificity

(2019) Daniele Musiani et al.   Science Signaling

Discovery of Potent and Selective Covalent Protein Arginine Methyl-transferase 5 (PRMT5) Inhibitors.

(2019) Hong Lin et al.   ACS Medicinal Chemistry Letters

Role of protein arginine methyltransferase 5 in human cancers

(2019) Wendi Xiao et al.   BIOMEDICINE & PHARMACOTHERAPY

Protein arginine methyltransferases: insights into the enzyme structure and mechanism at the atomic level

(2019) Sunil Kumar Tewary et al.   CELLULAR AND MOLECULAR LIFE SCIENCES

Cellular consequences of arginine methylation

(2019) Benjamin M. Lorton et al.   CELLULAR AND MOLECULAR LIFE SCIENCES

The regulation, functions and clinical relevance of arginine methylation

(2019) Ernesto Guccione et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Therapeutic Targeting of RNA Splicing Catalysis through Inhibition of Protein Arginine Methylation

(2019) Jia Yi Fong et al.   CANCER CELL

438OMETEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours

(2019) L L Siu et al.   ANNALS OF ONCOLOGY

Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signaling

(2018) Pengyu Jing et al.   CANCER LETTERS

Recent advances in targeting protein arginine methyltransferase enzymes in cancer therapy

(2018) Emily Smith et al.   EXPERT OPINION ON THERAPEUTIC TARGETS

Protein Arginine Methyltransferase 5 (PRMT5) as an Anticancer Target and Its Inhibitor Discovery

(2018) Yuanxiang Wang et al.   JOURNAL OF MEDICINAL CHEMISTRY

LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity

(2018) Zahid Q. Bonday et al.   ACS Medicinal Chemistry Letters

PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes

(2018) Pierre-Jacques Hamard et al.   Cell Reports

PRMT5 Circular RNA Promotes Metastasis of Urothelial Carcinoma of the Bladder through Sponging miR-30c to Induce Epithelial–Mesenchymal Transition

(2018) Xin Chen et al.   CLINICAL CANCER RESEARCH

Emerging and Re-Emerging Warheads for Targeted Covalent Inhibitors: Applications in Medicinal Chemistry and Chemical Biology

(2018) Matthias Gehringer et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A

(2018) John R. Horton et al.   JOURNAL OF MEDICINAL CHEMISTRY

PRMT5 is essential for B cell development and germinal center dynamics

(2018) Ludivine C. Litzler et al.   Nature Communications

Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation

(2018) Jingwei Shao et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

The story of protein arginine methylation: characterization, regulation, and function

(2017) Chao Peng et al.   Expert Review of Proteomics

Targeting protein arginine methyltransferase 5 in disease

(2017) André Richters   Future Medicinal Chemistry

Arginine Methylation: The Coming of Age

(2017) Roméo S. Blanc et al.   MOLECULAR CELL

PRMT5 as a druggable target for glioblastoma therapy

(2017) Yeshavanth Kumar Banasavadi-Siddegowda et al.   NEURO-ONCOLOGY

Elevated expression of protein arginine methyltransferase 5 predicts the poor prognosis of breast cancer

(2017) Ying Wu et al.   TUMOR BIOLOGY

A novel SHARPIN-PRMT5-H3R2me1 axis is essential for lung cancer cell invasion

(2017) Tingxiong Fu et al.   Oncotarget

Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth

(2016) L. Liu et al.   CANCER RESEARCH

Small Molecule Inhibitors of Protein Arginine Methyltransferases

(2016) Hao Hu et al.   EXPERT OPINION ON INVESTIGATIONAL DRUGS

Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase

(2016) Kyle V. Butler et al.   JOURNAL OF MEDICINAL CHEMISTRY

A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression

(2016) H Chen et al.   ONCOGENE

Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth

(2016) X Deng et al.   ONCOGENE

Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5

(2016) Konstantinos J. Mavrakis et al.   SCIENCE

MTAPdeletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells

(2016) Gregory V. Kryukov et al.   SCIENCE

MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis

(2016) Katya Marjon et al.   Cell Reports

Protein Arginine Methyltransferase 8: Tetrameric Structure and Protein Substrate Specificity

(2015) Wei-Chao Lee et al.   BIOCHEMISTRY

Chemical Biology of Protein Arginine Modifications in Epigenetic Regulation

(2015) Jakob Fuhrmann et al.   CHEMICAL REVIEWS

Histone H2A and H4 N-terminal Tails Are Positioned by the MEP50 WD Repeat Protein for Efficient Methylation by the PRMT5 Arginine Methyltransferase

(2015) Emmanuel S. Burgos et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2

(2015) Andrea Hadjikyriacou et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis

(2015) Fan Liu et al.   JOURNAL OF CLINICAL INVESTIGATION

The dual epigenetic role of PRMT5 in acute myeloid leukemia: gene activation and repression via histone arginine methylation

(2015) S S Tarighat et al.   LEUKEMIA

SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination

(2015) Dorothy Yanling Zhao et al.   NATURE

A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models

(2015) Elayne Chan-Penebre et al.   Nature Chemical Biology

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

(2015) Kenneth W. Duncan et al.   ACS Medicinal Chemistry Letters

PRMT9 is a Type II methyltransferase that methylates the splicing factor SAP145

(2015) Yanzhong Yang et al.   Nature Communications

Expression of PRMT5 in lung adenocarcinoma and its significance in epithelial-mesenchymal transition

(2014) Reem Ibrahim et al.   HUMAN PATHOLOGY

Enhanced Arginine Methylation of Programmed Cell Death 4 Protein during Nutrient Deprivation Promotes Tumor Cell Viability

(2014) Marta M. Fay et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Inhibition of Cardiomyocyte Hypertrophy by Protein Arginine Methyltransferase 5

(2014) Ming Chen et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Selective Inhibitors of Protein Methyltransferases

(2014) H. Ümit Kaniskan et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structural biology and chemistry of protein arginine methyltransferases

(2014) Matthieu Schapira et al.   MedChemComm

Structure of the Arginine Methyltransferase PRMT5-MEP50 Reveals a Mechanism for Substrate Specificity

(2013) Meng-Chiao Ho et al.   PLoS One

Arginine methylation controls growth regulation by E2F-1

(2012) Er-Chieh Cho et al.   EMBO JOURNAL

Human Protein Arginine Methyltransferase 7 (PRMT7) Is a Type III Enzyme Forming ω-NG-Monomethylated Arginine Residues

(2012) Cecilia I. Zurita-Lopez et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

HOXA9 Methylation by PRMT5 Is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules

(2012) S. Bandyopadhyay et al.   MOLECULAR AND CELLULAR BIOLOGY

Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance

(2012) Valentina Migliori et al.   NATURE STRUCTURAL & MOLECULAR BIOLOGY

Crystal structure of the human PRMT5:MEP50 complex

(2012) S. Antonysamy et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Purine 5′,8-cyclonucleoside lesions: chemistry and biology

(2011) Chryssostomos Chatgilialoglu et al.   CHEMICAL SOCIETY REVIEWS

Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation

(2011) Jung-Mao Hsu et al.   NATURE CELL BIOLOGY

A role for the arginine methylation of Rad9 in checkpoint control and cellular sensitivity to DNA damage

(2011) Wei He et al.   NUCLEIC ACIDS RESEARCH

Versatility of PRMT5-induced methylation in growth control and development

(2011) Vrajesh Karkhanis et al.   TRENDS IN BIOCHEMICAL SCIENCES

PRMT5 regulates Golgi apparatus structure through methylation of the golgin GM130

(2010) Zhongwei Zhou et al.   CELL RESEARCH

RioK1, a New Interactor of Protein Arginine Methyltransferase 5 (PRMT5), Competes with pICln for Binding and Modulates PRMT5 Complex Composition and Substrate Specificity

(2010) Gernot Guderian et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival

(2010) Alyssa M Krasinskas et al.   MODERN PATHOLOGY

The protein arginine methyltransferase family: an update about function, new perspectives and the physiological role in humans

(2009) S. S. Wolf   CELLULAR AND MOLECULAR LIFE SCIENCES

Preparation of Cyclonucleosides

(2009) Adam Mieczkowski et al.   CHEMICAL REVIEWS

Role of pICLn in Methylation of Sm Proteins by PRMT5

(2009) G. Scott Pesiridis et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

PRMT5 is required for cell-cycle progression and p53 tumor suppressor function

(2009) A. Scoumanne et al.   NUCLEIC ACIDS RESEARCH

The histone-binding protein COPR5 is required for nuclear functions of the protein arginine methyltransferase PRMT5

(2008) Matthieu Lacroix et al.   EMBO REPORTS