Evidence map›Paper›PMID 33990599›Full record

ArticleNature communications2021

Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity.

David S Rogawski, Jing Deng, Hao Li, Hongzhi Miao, Dmitry Borkin, Trupta Purohit, Jiho Song, Jennifer Chase, Shuangjiang Li, Juliano Ndoj and 20 more

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

Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
2.7field-weighted citation impact, top 9% 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

28 citing papers in PubMed, 43 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Review
  6. Article
  7. Investigating oncoprotein-mediated chromatin dysregulation inbioRxiv : the preprint server for biology · 2025
    Article
  8. Article
  9. Article
  10. Loss-of-function mutations of microRNA-142-3p promoteWorld journal of gastroenterology · 2025
    Article
  11. Article
  12. Lysine and arginine methylation of transcription factors.Cellular and molecular life sciences : CMLS · 2024
    Review
  13. Article
  14. Article
  15. Review
  16. Review
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  18. Article
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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

30 authors at 5 institutions in 2 countries.

David S Rogawski *Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Jing Deng *Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Hao Li *Department of Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0001-8495-8467
Hongzhi MiaoDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Dmitry BorkinDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Trupta PurohitDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Jiho SongDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Jennifer ChaseLife Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Shuangjiang LiDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Juliano NdojDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Szymon KlossowskiDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
EunGi KimDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Fengbiao MaoDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Bo ZhouDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
James RopaDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Marta Z KrotoskaDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Zhuang JinDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0002-8031-5680
Patricia ErnstDepartment of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.
Xiaomin FengDepartment of Pathology and Laboratory Medicine, Cincinnati Children's Hospital, Cincinnati, OH, USA.
Gang HuangDepartment of Pathology and Laboratory Medicine, Cincinnati Children's Hospital, Cincinnati, OH, USA.ORCID 0000-0002-5457-5358
Kenichi NishiokaDepartment of Internal Medicine Musashimurayama Hospital, Enoki 1-1-5, Musashimurayama, Tokyo, Japan.
Samantha KellyDivision of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Miao HeCollege of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Bo WenCollege of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Duxin SunCollege of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Andrew MunteanDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Yali DouDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID 0000-0002-4040-1429
Ivan MaillardLife Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Tomasz CierpickiDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA. tomaszc@umich.edu.ORCID 0000-0003-2058-0658
Jolanta GrembeckaDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA. jolantag@med.umich.edu.ORCID 0000-0002-6180-9095
University of Michigan · USCincinnati Children's Hospital Medical Center · USMusashi University · JPUniversity of Colorado Anschutz Medical Campus · USUniversity of Pennsylvania · US

Funding

REGULATION OF HEMATOPOIETIC CELL PRODUCTIONT32DK007519 · NIDDK · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI KAPLAN, MARK H · 1986 to 2020
$7.1M
Function of MLL in transcription regulationR01GM082856 · NIGMS · UNIVERSITY OF SOUTHERN CALIFORNIA · PI DOU, YALI · 2009 to 2023
$4.0M
Development of novel anti-leukemia agents targeting the menin-MLL interactionR01CA160467 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GREMBECKA, JOLANTA · 2011 to 2021
$3.4M
Structural insights into the MLL core complexesR01CA250329 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI CHO, UHN-SOO, DOU, YALI · 2020 to 2024
$3.0M
Development of ASH1L inhibitors for acute leukemiaR01CA244254 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GREMBECKA, JOLANTA · 2020 to 2024
$2.8M
Enhancer Dysregulation in AMLR01CA232263 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI DOU, YALI · 2019 to 2023
$2.7M
Molecular functions of the shelterin component ACD/TPP1 in somatic stem cells and tissue homeostasisR01AG050509 · NIA · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI KEEGAN, CATHERINE ELIZABETH, MAILLARD, IVAN · 2015 to 2019
$2.3M
Targeting NSD1 in leukemiaR01CA226759 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CIERPICKI, TOMASZ · 2019 to 2023
$2.3M
MLL Family Histone Methyltransferases in Myeloid LeukemiaR01CA224436 · NCI · UNIVERSITY OF COLORADO DENVER · PI ERNST, PATRICIA · 2018 to 2022
$2.1M
Development of small molecules targeting Ring1B-Bmi1 E3 ligase in leukemiaR01CA207272 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CIERPICKI, TOMASZ · 2016 to 2020
$2.0M
The role of the PAFc subunit Cdc73 in normal hematopoiesis and transformationR01HL136420 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI MUNTEAN, ANDREW GEORGE · 2018 to 2022
$1.9M
Targeting protein-protein interactions of Bmi1 oncoproteinR01CA201204 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GREMBECKA, JOLANTA · 2016 to 2018
$959k
NCI NIH HHS R01 CA160467NCI NIH HHS R01 CA201204NCI NIH HHS R01 CA207272NCI NIH HHS R01 CA224436NCI NIH HHS R01 CA226759NCI NIH HHS R01 CA232263NCI NIH HHS R01 CA244254NCI NIH HHS R01 CA250329NHLBI NIH HHS R01 HL136420NIA NIH HHS R01 AG050509NIDDK NIH HHS T32 DK007519NIGMS NIH HHS R01 GM082856
6 · The paper itself

Abstract

ASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.

Indexed as

AnimalsAntineoplastic AgentsCatalytic DomainCell Line, TumorCell Transformation, NeoplasticCrystallography, X-RayDNA-Binding ProteinsDrug DesignDrug DiscoveryEnzyme InhibitorsFemaleHistone-Lysine N-MethyltransferaseHumansLeukemiaMiceMice, Inbred C57BLAntineoplastic AgentsASH1L protein, humanAsh1l protein, mouseDNA-Binding ProteinsEnzyme InhibitorsHistone-Lysine N-MethyltransferaseKMT2A protein, humanKmt2a protein, mouseMyeloid-Lymphoid Leukemia ProteinRecombinant Fusion Proteins

Identifiers

PMID33990599
PMCPMC8121805
OpenAlexW3161615669

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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.