Discovery of a chemical probe for PRDM9

被引：29

作者：

Allali-Hassani, Abdellah ^{[1
]}

Szewczyk, Magdalena M. ^{[1
]}

Ivanochko, Danton ^{[1
,2
,3
]}

Organ, Shawna L. ^{[1
]}

Bok, Jabez ^{[4
]}

Ho, Jessica Sook Yuin ^{[4
]}

Gay, Florence P. N. ^{[4
]}

Li, Fengling ^{[1
]}

Blazer, Levi ^{[1
]}

Eram, Mohammad S. ^{[1
]}

Halabelian, Levon ^{[1
]}

Dilworth, David ^{[1
]}

Luciani, Genna M. ^{[1
]}

Lima-Fernandes, Evelyne ^{[1
]}

Wu, Qin ^{[1
]}

Loppnau, Peter ^{[1
]}

Palmer, Nathan ^{[4
]}

Talib, S. Zakiah A. ^{[4
]}

Brown, Peter J. ^{[1
]}

Schapira, Matthieu ^{[1
,5
]}

Kaldis, Philipp ^{[4
,6
]}

O'Hagan, Ronan C. ^{[7
]}

Guccione, Ernesto ^{[4
,8
,9
,10
,11
]}

Barsyte-Lovejoy, Dalia ^{[1
,12
]}

Arrowsmith, Cheryl H. ^{[1
,2
,3
]}

Sanders, John M. ^{[7
]}

Kattar, Solomon D. ^{[7
]}

Bennett, D. Jonathan ^{[7
]}

Nicholson, Benjamin ^{[7
]}

Vedadi, Masoud ^{[1
,5
]}

机构：

[1] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[2] Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada

[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada

[4] ASTAR, IMCB, Singapore, Singapore

[5] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada

[6] NUS, Dept Biochem, Singapore 117597, Singapore

[7] Merck & Co Inc, 2000 Galloping Hill Rd, Kenilworth, NJ 07033 USA

[8] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA

[9] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA

[10] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA

[11] Icahn Sch Med Mt Sinai, Mt Sinai Ctr Therapeut Discovery, New York, NY 10029 USA

[12] Nat Res Ctr, Akademijos 2, Vilnius, Lithuania

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷

基金：

巴西圣保罗研究基金会; 加拿大自然科学与工程研究理事会; 加拿大创新基金会;

关键词：

PR DOMAIN; HISTONE; GENE;

D O I：

10.1038/s41467-019-13652-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 (IC50: 80 +/- 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substratecompetitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

引用

页数：11

共 38 条

[1] Role of the active-site solvent in the thermodynamics of factor Xa ligand binding [J].

Abel, Robert ;

Young, Tom ;

Farid, Ramy ;

Berne, Bruce J. ;

Friesner, Richard A. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130 (09) :2817-2831

[2]

Altemose N, 2017, ELIFE, V6, DOI [10.7554/e.Life.28383, 10.7554/eLife.28383]

[3]

[Anonymous], 2000, Enzymes: A Practical Introduction to Structure, Mechanism, and Data Analysis

[4] PRDM9 Is a Major Determinant of Meiotic Recombination Hotspots in Humans and Mice [J].

Baudat, F. ;

Buard, J. ;

Grey, C. ;

Fledel-Alon, A. ;

Ober, C. ;

Przeworski, M. ;

Coop, G. ;

de Massy, B. .

SCIENCE, 2010, 327 (5967) :836-840

[5] PR Domain-containing Protein 7 (PRDM7) Is a Histone 3 Lysine 4 Trimethyltransferase [J].

Blazer, Levi L. ;

Lima-Fernandes, Evelyne ;

Gibson, Elisa ;

Eram, Mohammad S. ;

Loppnau, Peter ;

Arrowsmith, Cheryl H. ;

Schapira, Matthieu ;

Vedadi, Masoud .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (26) :13509-13519

[6] Structural Chemistry of the Histone Methyltransferases Cofactor Binding Site [J].

Campagna-Slater, Valerie ;

Mok, Man Wai ;

Nguyen, Kong T. ;

Feher, Mildos ;

Najmanovich, Rafael ;

Schapira, Matthieu .

JOURNAL OF CHEMICAL INFORMATION AND MODELING, 2011, 51 (03) :612-623

[7] Protein methyltransferase inhibitors as precision cancer therapeutics: a decade of discovery [J].

Copeland, Robert A. .

PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, 2018, 373 (1748)

[8] Protein methyltransferases as a target class for drug discovery [J].

Copeland, Robert A. ;

Solomon, Michael E. ;

Richon, Victoria M. .

NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (09) :724-732

[9] Homogeneous Assay for Target Engagement Utilizing Bioluminescent Thermal Shift [J].

Dart, Melanie L. ;

Machleidt, Thomas ;

Jost, Emily ;

Schwinn, Marie K. ;

Robers, Matthew B. ;

Shi, Ce ;

Kirkland, Thomas A. ;

Killoran, Michael P. ;

Wilkinson, Jennifer M. ;

Hartnett, James R. ;

Zimmerman, Kristopher ;

Wood, Keith V. .

ACS MEDICINAL CHEMISTRY LETTERS, 2018, 9 (06) :546-551

[10] Re-engineering the zinc fingers of PRDM9 reverses hybrid sterility in mice [J].

Davies, Benjamin ;

Hatton, Edouard ;

Altemose, Nicolas ;

Hussin, Julie G. ;

Pratto, Florencia ;

Zhang, Gang ;

Hinch, Anjali Gupta ;

Moralli, Daniela ;

Biggs, Daniel ;

Diaz, Rebeca ;

Preece, Chris ;

Li, Ran ;

Bitoun, Emmanuelle ;

Brick, Kevin ;

Green, Catherine M. ;

Amerini-Otero, R. Daniel C. ;

Myers, Simon R. ;

Donnelly, Peter .

NATURE, 2016, 530 (7589) :171-+

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