Evidence map›Paper›PMID 34155404›Full record

ArticleNature chemical biology2021

Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain.

Shirish Shukla, Weijiang Ying, Felicia Gray, Yiwu Yao, Miranda L Simes, Qingjie Zhao, Hongzhi Miao, Hyo Je Cho, Paula González-Alonso, Alyssa Winkler and 15 more

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

Article in Nature chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed
4.1field-weighted citation impact, top 5% 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

35 citing papers in PubMed, 66 citations in OpenAlex.

  1. Article
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  11. International journal of oncology · 2024
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  19. The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer.Journal of cancer research and clinical oncology · 2024
    Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

25 authors at 3 institutions in 2 countries.

Shirish Shukla *Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Weijiang Ying *Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Felicia Gray *Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Yiwu Yao *Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Miranda L Simes *Department of Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-0410-0864
Qingjie ZhaoDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Hongzhi MiaoDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Hyo Je ChoDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Paula González-AlonsoDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-5343-8300
Alyssa WinklerDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
George LundDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Trupta PurohitDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
EunGi KimDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Xiaotian ZhangDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Joshua M RayDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Shihan HeDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Caroline NikolaidisDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Juliano NdojDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Jingya WangDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Łukasz JaremkoBiological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.ORCID http://orcid.org/0000-0001-7684-9359
Mariusz JaremkoBiological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
Russell J H RyanDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-8174-3962
Monica L GuzmanDivision of Hematology and Medical Oncology, Leukemia Program, Weill Cornell Medicine/New York-Presbyterian Hospital, New York, NY, USA.ORCID http://orcid.org/0000-0002-9262-8246
Jolanta GrembeckaDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA. jolantag@umich.edu.ORCID http://orcid.org/0000-0002-6180-9095
Tomasz CierpickiDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA. tomaszc@umich.edu.ORCID http://orcid.org/0000-0003-2058-0658
University of Michigan · USKing Abdullah University of Science and Technology · SANewYork–Presbyterian Hospital · US

Funding

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
Development of ASH1L inhibitors for acute leukemiaR01CA244254 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GREMBECKA, JOLANTA · 2020 to 2024
$2.8M
Targeting NSD1 in leukemiaR01CA226759 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CIERPICKI, TOMASZ · 2019 to 2023
$2.3M
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
Targeting epigenetic reader GAS41R01CA240514 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI CIERPICKI, TOMASZ · 2020 to 2023
$2.0M
Targeting protein-protein interactions of Bmi1 oncoproteinR01CA201204 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI GREMBECKA, JOLANTA · 2016 to 2018
$959k
Oncogenic programs driven by Notch signaling in B-cell lymphomaK08CA208013 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI RYAN, RUSSELL JAMES HUBBARD · 2016 to 2020
$791k
NCI NIH HHS K08 CA208013NCI NIH HHS R01 CA160467NCI NIH HHS R01 CA201204NCI NIH HHS R01 CA207272NCI NIH HHS R01 CA226759NCI NIH HHS R01 CA240514NCI NIH HHS R01 CA244254
6 · The paper itself

Abstract

Polycomb repressive complex 1 (PRC1) is an essential chromatin-modifying complex that monoubiquitinates histone H2A and is involved in maintaining the repressed chromatin state. Emerging evidence suggests PRC1 activity in various cancers, rationalizing the need for small-molecule inhibitors with well-defined mechanisms of action. Here, we describe the development of compounds that directly bind to RING1B-BMI1, the heterodimeric complex constituting the E3 ligase activity of PRC1. These compounds block the association of RING1B-BMI1 with chromatin and inhibit H2A ubiquitination. Structural studies demonstrate that these inhibitors bind to RING1B by inducing the formation of a hydrophobic pocket in the RING domain. Our PRC1 inhibitor, RB-3, decreases the global level of H2A ubiquitination and induces differentiation in leukemia cell lines and primary acute myeloid leukemia (AML) samples. In summary, we demonstrate that targeting the PRC1 RING domain with small molecules is feasible, and RB-3 represents a valuable chemical tool to study PRC1 biology.

Indexed as

Cell DifferentiationDose-Response Relationship, DrugHumansK562 CellsModels, MolecularMolecular StructurePolycomb Repressive Complex 1Small Molecule LibrariesUbiquitinationPolycomb Repressive Complex 1Small Molecule Libraries

Identifiers

PMID34155404
PMCPMC8238916
OpenAlexW3177272482

What OpenQuestion holds

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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.