Discovery of a chemical probe for PRDM9.

Crystallography, X-Ray DNA Methylation / drug effects Drug Discovery / methods Enzyme Inhibitors / chemistry HEK293 Cells Histone-Lysine N-Methyltransferase / antagonists & inhibitors Histones / metabolism Humans Inhibitory Concentration 50 Molecular Dynamics Simulation Molecular Probes / chemistry Protein Domains S-Adenosylmethionine / metabolism

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
17 12 2019
Historique:
received: 22 04 2019
accepted: 15 11 2019
entrez: 19 12 2019
pubmed: 19 12 2019
medline: 9 4 2020
Statut: epublish

Résumé

PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC

Identifiants

DOI: 10.1038/s41467-019-13652-x PMID: 31848333 PMC: PMC6917776
pubmed: 31848333
doi: 10.1038/s41467-019-13652-x
pii: 10.1038/s41467-019-13652-x
pmc: PMC6917776
doi:

Substances chimiques

Enzyme Inhibitors 0
Histones 0
Molecular Probes 0
histone H3 trimethyl Lys4 0
S-Adenosylmethionine 7LP2MPO46S
Histone-Lysine N-Methyltransferase EC 2.1.1.43
PRDM9 protein, human EC 2.1.1.43

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

5759

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Auteurs

Abdellah Allali-Hassani (A)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Magdalena M Szewczyk (MM)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Danton Ivanochko (D)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.

Shawna L Organ (SL)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Jabez Bok (J)

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Jessica Sook Yuin Ho (JSY)

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
ORCID: 0000-0003-2234-2602

Florence P H Gay (FPH)

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

Fengling Li (F)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Levi Blazer (L)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Mohammad S Eram (MS)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Levon Halabelian (L)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
ORCID: 0000-0003-4361-3619

David Dilworth (D)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
ORCID: 0000-0001-5557-9476

Genna M Luciani (GM)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
ORCID: 0000-0001-8107-2708

Evelyne Lima-Fernandes (E)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
ORCID: 0000-0002-3628-9745

Qin Wu (Q)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Peter Loppnau (P)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.

Nathan Palmer (N)

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.

S Zakiah A Talib (SZA)

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
ORCID: 0000-0002-6063-254X

Peter J Brown (PJ)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
ORCID: 0000-0002-8454-0367

Matthieu Schapira (M)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
ORCID: 0000-0002-1047-3309

Philipp Kaldis (P)

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
National University of Singapore (NUS), Department of Biochemistry, 117597, Singapore, Singapore.
ORCID: 0000-0002-7247-7591

Ronan C O'Hagan (RC)

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.

Ernesto Guccione (E)

Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Department of Pharmacological Sciences and Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Dalia Barsyte-Lovejoy (D)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
Nature Research Center, Vilnius, Akademijos, 2, Lithuania.
ORCID: 0000-0002-6560-9621

Cheryl H Arrowsmith (CH)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada.
Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 2M9, Canada.
ORCID: 0000-0002-4971-3250

John M Sanders (JM)

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.
ORCID: 0000-0002-3788-4220

Solomon D Kattar (SD)

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.

D Jonathan Bennett (DJ)

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA.
ORCID: 0000-0003-0163-7479

Benjamin Nicholson (B)

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. benjamin.nicholson@merck.com.

Masoud Vedadi (M)

Structural Genomics Consortium, University of Toronto, Toronto, ON, M5G 1L7, Canada. m.vedadi@utoronto.ca.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, M5S 1A8, Canada. m.vedadi@utoronto.ca.
ORCID: 0000-0002-0574-0169

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Classifications MeSH

questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › One-carbon group transferases › Methyltransferases › Protein Methyltransferases › Histone méthyltransférases › Histone-lysine N-methyltransferase › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Concentration inhibitrice 50 › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Sciences de l'information › Méthodologies informatiques › Simulation numérique › Simulation de dynamique moléculaire › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Sondes moléculaires › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure tertiaire des protéines › Domaines protéiques › Discovery of a chemical probe for PRDM9.
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléosides › Ribonucléosides › Adénosine › Adémétionine › Discovery of a chemical probe for PRDM9.