Evidence map›Paper›PMID 31978781›Full record

ArticleEuropean journal of medicinal chemistry2020

Identification of DOT1L inhibitors by structure-based virtual screening adapted from a nucleoside-focused library.

Garrett S Gibbons, Amarraj Chakraborty, Sierrah M Grigsby, Afoma C Umeano, Chenzhong Liao, Omar Moukha-Chafiq, Vibha Pathak, Bini Mathew, Young-Tae Lee, Yali Dou and 4 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in European journal of medicinal chemistry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
1.7field-weighted citation impact, top 16% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed, 22 citations in OpenAlex.

  1. Review
  2. Review
  3. Review
  4. Review
  5. Frontiers in pharmacology · 2024
    Article
  6. Review
  7. Review
  8. Article
  9. Review
  10. Article
  11. Review
  12. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 5 institutions in 1 country.

Garrett S GibbonsDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Amarraj ChakrabortyDepartment of Chemistry and Biochemistry, The University of Alabama, 250 Hackberry Lane, Tuscaloosa, AL, 35487, USA.
Sierrah M GrigsbyDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Afoma C UmeanoDepartment of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA.
Chenzhong LiaoDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Omar Moukha-ChafiqSouthern Research Institute, Drug Discovery Division, Birmingham, AL, 35205, USA.
Vibha PathakSouthern Research Institute, Drug Discovery Division, Birmingham, AL, 35205, USA.
Bini MathewSouthern Research Institute, Drug Discovery Division, Birmingham, AL, 35205, USA.
Young-Tae LeeDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Yali DouDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Stephan C SchürerDepartment of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA; Center for Computational Science, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA; Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, 33136, USA.
Robert C ReynoldsDivision of Hematology and Oncology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Timothy S SnowdenDepartment of Chemistry and Biochemistry, The University of Alabama, 250 Hackberry Lane, Tuscaloosa, AL, 35487, USA. Electronic address: snowden@ua.edu.
Zaneta Nikolovska-ColeskaDepartment of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA; Rogel Cancer Center at University of Michigan Medical School, Ann Arbor, MI, 48109, USA. Electronic address: zanetan@med.umich.edu.
University of Michigan · USSouthern Research Institute · USUniversity of Alabama · USUniversity of Miami · USUniversity of Alabama at Birmingham · US

Funding

Data Coordination and Integration Center for LINCS-BD2KU54HL127624 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI MA'AYAN, AVI, SCHURER, STEPHAN C · 2014 to 2019
$23.5M
Resource Dissemination and Outreach Center for Illuminating the Druggable GenomeU24TR002278 · NCATS · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI SCHURER, STEPHAN C, SKLAR, LARRY A. · 2018 to 2023
$3.7M
Pilot-Scale Libraries Based on Nucleoside Templates for the ML InitiativeP41GM086163 · NIGMS · SOUTHERN RESEARCH INSTITUTE · PI REYNOLDS, ROBERT C · 2008 to 2010
$1.7M
Novel selective small-molecule inhibitors of Mcl-1 proteinR01CA149442 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI NIKOLOVSKA-COLESKA, ZANETA · 2010 to 2014
$1.5M
Novel Therapeutics Targeting CARM1 Overexpression in AMLF31CA228331 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI UMEANO, AFOMA CHINYELU · 2018 to 2022
$203k
NCATS NIH HHS U24 TR002278NCI NIH HHS F31 CA228331NCI NIH HHS R01 CA149442NHLBI NIH HHS U54 HL127624NIGMS NIH HHS P41 GM086163
6 · The paper itself

Abstract

Disruptor of Telomeric Silencing 1-Like (DOT1L), the sole histone H3 lysine 79 (H3K79) methyltransferase, is required for leukemogenic transformation in a subset of leukemias bearing chromosomal translocations of the Mixed Lineage Leukemia (MLL) gene, as well as other cancers. Thus, DOT1L is an attractive therapeutic target and discovery of small molecule inhibitors remain of high interest. Herein, we are presenting screening results for a unique focused library of 1200 nucleoside analogs originally produced under the aegis of the NIH Pilot Scale Library Program. The complete nucleoside set was screened virtually against DOT1L, resulting in 210 putative hits. In vitro screening of the virtual hits resulted in validation of 11 compounds as DOT1L inhibitors clustered into two distinct chemical classes, adenosine-based inhibitors and a new chemotype that lacks adenosine. Based on the developed DOT1L ligand binding model, a structure-based design strategy was applied and a second-generation of non-nucleoside DOT1L inhibitors was developed. Newly synthesized compound 25 was the most potent DOT1L inhibitor in the new series with an IC

Indexed as

Cell ProliferationAnimalsBone MarrowComputer SimulationEnzyme InhibitorsHigh-Throughput Screening AssaysHistone-Lysine N-MethyltransferaseLeukemia, ExperimentalMiceNucleosidesStructure-Activity RelationshipTriazolesDot1l protein, mouseEnzyme InhibitorsHistone-Lysine N-MethyltransferaseNucleosidesTriazolesDOT1LHistone methyltransferaseMolecular modelingSmall-molecule inhibitorsStructure-based virtual screeningSynthesis

Identifiers

PMID31978781
PMCPMC7646624
OpenAlexW2998302660

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.