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Literature DB >> 28835804

Design of KDM4 Inhibitors with Antiproliferative Effects in Cancer Models.

Young K Chen¹, Tiziana Bonaldi², Alessandro Cuomo², Joselyn R Del Rosario¹, David J Hosfield³, Toufike Kanouni¹, Shih-Chu Kao⁴, Chon Lai¹, Neethan A Lobo⁴, Jennifer Matuszkiewicz¹, Andrew McGeehan⁴, Shawn M O'Connell¹, Lihong Shi¹, Jeffrey A Stafford¹, Ryan K Stansfield¹, James M Veal¹, Michael S Weiss⁴, Natalie Y Yuen⁴, Michael B Wallace¹.

Abstract

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.

Entities: Chemical Disease

Keywords: Epigenetics; JMJD2; KDM4; cancer; histone demethylase; synthesis

Year: 2017 PMID： 28835804 PMCID： PMC5554903 DOI： 10.1021/acsmedchemlett.7b00220

Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345

35 in total

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Journal: Cancer Cell Date: 2015-07-13 Impact factor: 31.743

2. The transcriptional repressor JHDM3A demethylates trimethyl histone H3 lysine 9 and lysine 36.

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Journal: Nature Date: 2006-05-28 Impact factor: 49.962

3. Targeting Histone Demethylases: A New Avenue for the Fight against Cancer.

Authors: Dante Rotili; Antonello Mai
Journal: Genes Cancer Date: 2011-06

4. Identification of a novel gene, GASC1, within an amplicon at 9p23-24 frequently detected in esophageal cancer cell lines.

Authors: Z Q Yang; I Imoto; Y Fukuda; A Pimkhaokham; Y Shimada; M Imamura; S Sugano; Y Nakamura; J Inazawa
Journal: Cancer Res Date: 2000-09-01 Impact factor: 12.701

5. Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives.

Authors: Susan M Westaway; Alex G S Preston; Michael D Barker; Fiona Brown; Jack A Brown; Matthew Campbell; Chun-Wa Chung; Hawa Diallo; Clement Douault; Gerard Drewes; Robert Eagle; Laurie Gordon; Carl Haslam; Thomas G Hayhow; Philip G Humphreys; Gerard Joberty; Roy Katso; Laurens Kruidenier; Melanie Leveridge; John Liddle; Julie Mosley; Marcel Muelbaier; Rebecca Randle; Inma Rioja; Anne Rueger; Gail A Seal; Robert J Sheppard; Onkar Singh; Joanna Taylor; Pamela Thomas; Douglas Thomson; David M Wilson; Kevin Lee; Rab K Prinjha
Journal: J Med Chem Date: 2016-01-15 Impact factor: 7.446

6. Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells.

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Journal: Carcinogenesis Date: 2013-05-22 Impact factor: 4.944

7. Hypoxia drives transient site-specific copy gain and drug-resistant gene expression.

Authors: Joshua C Black; Elnaz Atabakhsh; Jaegil Kim; Kelly M Biette; Capucine Van Rechem; Brendon Ladd; Paul D Burrowes; Carlos Donado; Hamid Mattoo; Benjamin P Kleinstiver; Bing Song; Grasiella Andriani; J Keith Joung; Othon Iliopoulos; Cristina Montagna; Shiv Pillai; Gad Getz; Johnathan R Whetstine
Journal: Genes Dev Date: 2015-05-15 Impact factor: 11.361

8. Structure Property Relationships of Carboxylic Acid Isosteres.

Authors: Pierrik Lassalas; Bryant Gay; Caroline Lasfargeas; Michael J James; Van Tran; Krishna G Vijayendran; Kurt R Brunden; Marisa C Kozlowski; Craig J Thomas; Amos B Smith; Donna M Huryn; Carlo Ballatore
Journal: J Med Chem Date: 2016-03-30 Impact factor: 7.446

9. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer.

Authors: G Liu; A Bollig-Fischer; B Kreike; M J van de Vijver; J Abrams; S P Ethier; Z-Q Yang
Journal: Oncogene Date: 2009-09-28 Impact factor: 9.867

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

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Journal: Nature Date: 2012-08-16 Impact factor: 49.962

21 in total

1. Computational Prediction of the Binding Pose of Metal-Binding Pharmacophores.

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Journal: ACS Med Chem Lett Date: 2022-02-24 Impact factor: 4.345

Review 2. Recent Advances with KDM4 Inhibitors and Potential Applications.

Authors: Qiong Wu; Brandon Young; Yan Wang; Andrew M Davidoff; Zoran Rankovic; Jun Yang
Journal: J Med Chem Date: 2022-07-15 Impact factor: 8.039

3. Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma.

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Journal: Sci Transl Med Date: 2022-07-13 Impact factor: 19.319

4. Histone Lysine Methylation Dynamics Control EGFR DNA Copy-Number Amplification.

Authors: Thomas L Clarke; Ran Tang; Damayanti Chakraborty; Capucine Van Rechem; Fei Ji; Sweta Mishra; Anqi Ma; H Ümit Kaniskan; Jian Jin; Michael S Lawrence; Ruslan I Sadreyev; Johnathan R Whetstine
Journal: Cancer Discov Date: 2019-11-27 Impact factor: 38.272

5. The JmjN domain as a dimerization interface and a targeted inhibitor of KDM4 demethylase activity.

Authors: May Levin; Michal Stark; Yehuda G Assaraf
Journal: Oncotarget Date: 2018-03-30

6. Small molecule KDM4s inhibitors as anti-cancer agents.

Authors: Hongzhi Lin; Qihang Li; Qi Li; Jie Zhu; Kai Gu; Xueyang Jiang; Qianqian Hu; Feng Feng; Wei Qu; Yao Chen; Haopeng Sun
Journal: J Enzyme Inhib Med Chem Date: 2018-12 Impact factor: 5.051

7. C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays.

Authors: Yann-Vaï Le Bihan; Rachel M Lanigan; Butrus Atrash; Mark G McLaughlin; Srikannathasan Velupillai; Andrew G Malcolm; Katherine S England; Gian Filippo Ruda; N Yi Mok; Anthony Tumber; Kathy Tomlin; Harry Saville; Erald Shehu; Craig McAndrew; LeAnne Carmichael; James M Bennett; Fiona Jeganathan; Paul Eve; Adam Donovan; Angela Hayes; Francesca Wood; Florence I Raynaud; Oleg Fedorov; Paul E Brennan; Rosemary Burke; Rob L M van Montfort; Olivia W Rossanese; Julian Blagg; Vassilios Bavetsias
Journal: Eur J Med Chem Date: 2019-05-17 Impact factor: 6.514