ArticleNature cancer2021
Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.
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Article in Nature cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 173 papers.
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173citing papers in PubMed
14.8field-weighted citation impact, top 1% of its field
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Who cites it
173 citing papers in PubMed, 262 citations in OpenAlex.
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- Epigenetic Regulation of Ferroptosis in Inflammation: Molecular Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Interpretable distillation reveals that deep learning splicing models suffer from pervasive confounders and blind spots.Genome biology · 2026Article
- SUMOylation fine-tunes DNMT1 to silence viral mimicry transcripts.Nature genetics · 2026Article
- SUMOylation enhances DNMT1 function to repress mega-intergenic RNAs and viral mimicry.Nature genetics · 2026Article
- [Research Advances on Mechanisms and Interventions of DNA Methylation-Regulated Aging-Related Imbalance in Bone Metabolism].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2026Review
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- Advances in skin aging: integrating epigenetic, cellular, and immune mechanisms for targeted therapy.Immunity & ageing : I & A · 2026Review
- Reduced Maintenance DNA Methylation Thresholds Enable Sensitive Reporter Assays for UHRF1 and DNMT1 Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- CDCA7 targets LSH to DNA maintenance methylation in S phase and transcription regulation in interphase via two distinct DNA-binding modes.Nucleic acids research · 2026Article
- Recent Advances in Searching for DNMT Inhibitors and Their Potential Application in Treating Human Diseases.International journal of molecular sciences · 2026Review
- Review
- DAXX promotes SUMOylation of chromatin-trapped DNMT1.Journal of biochemistry · 2026Article
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- Tumor cell intrinsic mechanisms of immune escape.Cell communication and signaling : CCS · 2026Review
- DNMT inhibitor ameliorates hyperglycemia and renal inflammation partially via reversing hypermethylation-induced Klotho suppression in diabetic mice.Clinical epigenetics · 2026Article
- DNMT3A in cancer: from epigenetic writer to oncogenic driver.Clinical epigenetics · 2026Review
- Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML.Blood advances · 2026Article
113 more citing papers are in PubMed but not listed here.
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Authors and funding
62 authors at 7 institutions in 3 countries.
Melissa B PappalardiCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.ORCID 0000-0001-8457-1625
Kathryn KeenanCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Mark CockerillDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Wendy A KellnerCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Alexandra StowellDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Christian SherkCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Kristen WongCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Sarath PathuriDepartment of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jacques BriandMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Michael SteidelCellzome GmbH, Functional Genomics, GlaxoSmithKline, Heidelberg, Germany.
Philip ChapmanDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Arthur GroyFuture Pipeline Discovery, GlaxoSmithKline, Collegeville, PA, USA.
Ashley K WisemanCenter for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA.
Charles F McHughCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Nino CampobassoMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.ORCID 0000-0003-3419-2840
Alan P GravesMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Emma FairweatherDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Thilo WernerCellzome GmbH, Functional Genomics, GlaxoSmithKline, Heidelberg, Germany.
Ali RaoofDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Roger J ButlinDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Lourdes RuedaCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
John R HortonDepartment of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0001-9749-8068
David T FosbennerCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Cunyu ZhangCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Jessica L HandlerCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Morris MuliaditanDrug Metabolism and Pharmacokinetics Modelling, GlaxoSmithKline, Stevenage, UK.
Makda MebrahtuMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Jon-Paul JaworskiMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Dean E McNultyMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Charlotte BurtDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
H Christian EberlCellzome GmbH, Functional Genomics, GlaxoSmithKline, Heidelberg, Germany.ORCID 0000-0002-4159-5958
Amy N TaylorMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Thau HoMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Susan MerrihewCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Shawn W FoleyCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Anna RutkowskaCellzome GmbH, Functional Genomics, GlaxoSmithKline, Heidelberg, Germany.
Mei LiCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Stuart P RomerilCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Kristin GoldbergDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Xing ZhangDepartment of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Christopher S KershawDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Marcus BantscheffCellzome GmbH, Functional Genomics, GlaxoSmithKline, Heidelberg, Germany.ORCID 0000-0002-8343-8977
Anthony J JurewiczMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Elisabeth MinthornCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Paola GrandiCellzome GmbH, Functional Genomics, GlaxoSmithKline, Heidelberg, Germany.
Mehul PatelMedicinal Science & Technology, GlaxoSmithKline, Collegeville, PA, USA.
Andrew B BenowitzFuture Pipeline Discovery, GlaxoSmithKline, Collegeville, PA, USA.
Helai P MohammadCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Aidan G GilmartinFuture Pipeline Discovery, GlaxoSmithKline, Collegeville, PA, USA.
Rab K PrinjhaCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.ORCID 0000-0002-2666-3326
Donald OgilvieDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Christopher CarpenterCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Dirk HeerdingCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Stephen B BaylinDepartment of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA.
Peter A JonesCenter for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA.ORCID 0000-0001-8309-4767
Xiaodong ChengDepartment of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0002-6967-6362
Bryan W KingCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Juan I LuengoCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Allan M JordanDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.ORCID 0000-0003-3449-3993
Ian WaddellDrug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Ryan G KrugerCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Michael T McCabeCancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.ORCID 0000-0001-5715-9563
GlaxoSmithKline (United States) · USUniversity of Manchester · GBGlaxoSmithKline (Germany) · DEThe University of Texas MD Anderson Cancer Center · USVan Andel Institute · USGlaxoSmithKline (United Kingdom) · GBSidney Kimmel Comprehensive Cancer Center · US
Funding
Targeting DNA Methylation and the Cancer EpigenomeR35CA209859 · NCI · VAN ANDEL RESEARCH INSTITUTE · PI PETER A JONES · 2017 to 2026
$11.9MEpigenetic regulations of DNA and histone methylation and deMethylation: Structures and MechanismsR35GM134744 · NIGMS · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Xiaodong Cheng · 2020 to 2026
$4.5MCancer Research UK C480/A11411Cancer Research UK C5759/A17098NCI NIH HHS R35 CA209859NIGMS NIH HHS R35 GM134744
Abstract
DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia.
Indexed as
AzacitidineLeukemia, Myeloid, AcuteAnimalsDecitabineDNADNA MethylationDNA Modification MethylasesMiceAzacitidineDecitabineDNADNA Modification Methylases
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34790902PMC
PMC8594913OpenAlex
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