Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models

被引：56

作者：

Chen, Young K. ^{[1
]}

Bonaldi, Tiziana ^{[3
]}

Cuomo, Alessandro ^{[3
]}

Del Rosario, Joselyn R. ^{[1
]}

Hosfield, David J. ^{[4
]}

Kanouni, Toufike ^{[1
]}

Kao, Shih-chu ^{[2
,5
]}

Lai, Chon ^{[1
]}

Lobo, Neethan A. ^{[2
]}

Matuszkiewicz, Jennifer ^{[1
]}

McGeehan, Andrew ^{[2
]}

O'Connell, Shawn M. ^{[1
,6
]}

Shi, Lihong ^{[1
]}

Stafford, Jeffrey A. ^{[1
,7
]}

Stansfield, Ryan K. ^{[1
,7
]}

Veal, James M. ^{[1
,7
]}

Weiss, Michael S. ^{[2
,8
]}

Yuen, Natalie Y. ^{[2
]}

Wallace, Michael B. ^{[1
]}

机构：

[1] Celgene Quanticel Res, 10300 Campus Point Dr,Suite 100, San Diego, CA 92121 USA

[2] Celgene Quanticel Res, 1500 Owens St,Suite 500, San Francisco, CA 94158 USA

[3] European Inst Oncol, Dept Expt Oncol, Via Adamello 16, I-20139 Milan, Italy

[4] Univ Chicago, Ben May Dept Canc Res, 929 East 57th St, Chicago, IL 60637 USA

[5] Benitec Biopharma, 3940 Trust Way, Hayward, CA 94545 USA

[6] Pfizer Inc, Epigenet, Oncol R&D, 10724 Sci Ctr Dr, San Diego, CA 92121 USA

[7] Jecure Therapeut Inc, 4757 Nexus Ctr Dr,Suite 150, San Diego, CA 92121 USA

[8] Bristol Myers Squibb, 700 Bay Rd,Suite A, Redwood City, CA 94063 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2017年 / 8卷 / 08期

关键词：

Epigenetics; histone demethylase; KDM4; JMJD2; synthesis; cancer; HISTONE H3; BREAST-CANCER; COPY GAIN; DEMETHYLASES; GASC1; GENE; METHYLATION; PREVENTION; LYSINE-9; THERAPY;

D O I：

10.1021/acsmedchemlett.7b00220

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.

引用

页码：869 / 874

页数：6

共 37 条

[1] Hypoxia drives transient site-specific copy gain and drug-resistant gene expression [J].

Black, Joshua C. ;

Atabakhsh, Elnaz ;

Kim, Jaegil ;

Biette, Kelly M. ;

Van Rechem, Capucine ;

Ladd, Brendon ;

Burrowes, Paul D. ;

Donado, Carlos ;

Mattoo, Hamid ;

Kleinstiver, Benjamin P. ;

Song, Bing ;

Andriani, Grasiella ;

Joung, J. Keith ;

Iliopoulos, Othon ;

Montagna, Cristina ;

Pillai, Shiv ;

Getz, Gad ;

Whetstine, Johnathan R. .

GENES & DEVELOPMENT, 2015, 29 (10) :1018-1031

[2] KDM4A Lysine Demethylase Induces Site-Specific Copy Gain and Rereplication of Regions Amplified in Tumors [J].

Black, Joshua C. ;

Manning, Amity L. ;

Van Rechem, Capucine ;

Kim, Jaegil ;

Ladd, Brendon ;

Cho, Juok ;

Pineda, Cristiana M. ;

Murphy, Nancy ;

Daniels, Danette L. ;

Montagna, Cristina ;

Lewis, Peter W. ;

Glass, Kimberly ;

Allis, C. David ;

Dyson, Nicholas J. ;

Getz, Gad ;

Whetstine, Johnathan R. .

CELL, 2013, 154 (03) :541-555

[3] A combination of different mass spectroscopic techniques for the analysis of dynamic changes of histone modifications [J].

Bonaldi, T ;

Imhof, A ;

Regula, JT .

PROTEOMICS, 2004, 4 (05) :1382-1396

[4] The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3 [J].

Cloos, Paul A. C. ;

Christensen, Jesper ;

Agger, Karl ;

Maiolica, Alessio ;

Rappsilber, Juri ;

Antal, Torben ;

Hansen, Klaus H. ;

Helin, Kristian .

NATURE, 2006, 442 (7100) :307-311

[5] Distinct and Combinatorial Functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in Mouse Embryonic Stem Cell Identity [J].

Das, Partha Pratim ;

Shao, Zhen ;

Beyaz, Semir ;

Apostolou, Eftychia ;

Pinello, Luca ;

De Los Angeles, Alejandro ;

O'Brien, Kassandra ;

Atsma, Jennifer Marino ;

Fujiwara, Yuko ;

Minh Nguyen ;

Ljuboja, Damir ;

Guo, Guoji ;

Woo, Andrew ;

Yuan, Guo-Cheng ;

Onder, Tamer ;

Daley, George ;

Hochedlinger, Konrad ;

Kim, Jonghwan ;

Orkin, Stuart H. .

MOLECULAR CELL, 2014, 53 (01) :32-48

[6] Histone demethylases in chromatin biology and beyond [J].

Dimitrova, Emilia ;

Turberfield, Anne H. ;

Klose, Robert J. .

EMBO REPORTS, 2015, 16 (12) :1620-1639

[7]

Durkin K., US, Patent No. [2010/0160682, 20100160682]

[8] The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36 [J].

Klose, Robert J. ;

Yamane, Kenichi ;

Bae, Yangjin ;

Zhang, Dianzheng ;

Erdjument-Bromage, Hediye ;

Tempst, Paul ;

Wong, Jiemin ;

Zhang, Yi .

NATURE, 2006, 442 (7100) :312-316

[9] Chromatin modifications and their function [J].

Kouzarides, Tony .

CELL, 2007, 128 (04) :693-705

[10] A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response [J].

Kruidenier, Laurens ;

Chung, Chun-wa ;

Cheng, Zhongjun ;

Liddle, John ;

Che, KaHing ;

Joberty, Gerard ;

Bantscheff, Marcus ;

Bountra, Chas ;

Bridges, Angela ;

Diallo, Hawa ;

Eberhard, Dirk ;

Hutchinson, Sue ;

Jones, Emma ;

Katso, Roy ;

Leveridge, Melanie ;

Mander, Palwinder K. ;

Mosley, Julie ;

Ramirez-Molina, Cesar ;

Rowland, Paul ;

Schofield, Christopher J. ;

Sheppard, Robert J. ;

Smith, Julia E. ;

Swales, Catherine ;

Tanner, Robert ;

Thomas, Pamela ;

Tumber, Anthony ;

Drewes, Gerard ;

Oppermann, Udo ;

Patel, Dinshaw J. ;

Lee, Kevin ;

Wilson, David M. .

NATURE, 2012, 488 (7411) :404-408

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