ArticleACS medicinal chemistry letters2016
Optimization of a Fragment-Based Screening Hit toward Potent DOT1L Inhibitors Interacting in an Induced Binding Pocket.
Article in ACS medicinal chemistry letters, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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Who cites it
21 citing papers in PubMed.
- Design, synthesis and evaluation of pyrimidinobenzylamide and pyrimidinothiophenamide derivatives as inhibitors of DOT1L and related epigenetic targets DNMT3a, PRMT4 and other HMTs.RSC medicinal chemistry · 2025Article
- Discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer.Acta pharmaceutica Sinica. B · 2024Article
- Lysine methyltransferase inhibitors: where we are now.RSC chemical biology · 2022Review
- Targeting the histone H3 lysine 79 methyltransferase DOT1L in MLL-rearranged leukemias.Journal of hematology & oncology · 2022Review
- Histone Methyltransferase DOT1L as a Promising Epigenetic Target for Treatment of Solid Tumors.Frontiers in genetics · 2022Review
- Discovery of Cofactor Competitive Inhibitors against the Human Methyltransferase Fibrillarin.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein.Molecules (Basel, Switzerland) · 2021Article
- Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.Nature reviews. Drug discovery · 2021Review
- Quadruple Target Evaluation of Diversity-Optimized Halogen-Enriched Fragments (HEFLibs) Reveals Substantial Ligand Efficiency for AP2-Associated Protein Kinase 1 (AAK1).Frontiers in chemistry · 2021Article
- Identification of DOT1L inhibitors by structure-based virtual screening adapted from a nucleoside-focused library.European journal of medicinal chemistry · 2020Article
- New Potent DOT1L Inhibitors forACS medicinal chemistry letters · 2019Article
- Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor.Molecules (Basel, Switzerland) · 2019Review
- Article
- Chemical and Biochemical Perspectives of Protein Lysine Methylation.Chemical reviews · 2018Review
- Disruptor of telomeric silencing 1-like (DOT1L): disclosing a new class of non-nucleoside inhibitors by means of ligand-based and structure-based approaches.Journal of computer-aided molecular design · 2018Article
- Inhibitors of Protein Methyltransferases and Demethylases.Chemical reviews · 2018Review
- Preclinical Pharmacokinetics and Pharmacodynamics of Pinometostat (EPZ-5676), a First-in-Class, Small Molecule S-Adenosyl Methionine Competitive Inhibitor of DOT1L.European journal of drug metabolism and pharmacokinetics · 2017Review
- Recent progress in developing selective inhibitors of protein methyltransferases.Current opinion in chemical biology · 2017Review
- Discovery of Potent, Selective, and Structurally Novel Dot1L Inhibitors by a Fragment Linking Approach.ACS medicinal chemistry letters · 2017Article
- DNA Methylation Targeting: The DNMT/HMT Crosstalk Challenge.Biomolecules · 2017Review
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mixed lineage leukemia (MLL) gene rearrangement induces leukemic transformation by ectopic recruitment of disruptor of telomeric silencing 1-like protein (DOT1L), a lysine histone methyltransferase, leading to local hypermethylation of H3K79 and misexpression of genes (including HoxA), which drive the leukemic phenotype. A weak fragment-based screening hit identified by SPR was cocrystallized with DOT1L and optimized using structure-based ligand optimization to yield compound 8 (IC50 = 14 nM). This series of inhibitors is structurally not related to cofactor SAM and is not interacting within the SAM binding pocket but induces a pocket adjacent to the SAM binding site.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.