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Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2

Renato Ferreira de Freitas, Yanli Liu, Magdalena Szewczyk, Naimee Mehta, Fengling Li, David McLeod, Carlos Zepeda-Velázquez, David Dilworth, Ronan Hanley, Elisa Gibson, Peter Brown, Rima Al-Awar, Lindsey Ingerman James, Cheryl Arrowsmith, Dalia Barsyte-Lovejoy, Jinrong Min, Masoud Vedadi, Matthieu Schapira, Abdellah Allali-Hassani,

ABSTRACT Increased activity of the lysine methyltrans-ferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of ... Read more >>

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Rational Design and Synthesis of Selective PRMT4 Inhibitors: a New Chemotype for Development of Cancer Therapeutics

Mathew Sutherland, Alice Li, Anissa Kaghad, Dimitrios Panagopoulos, Fengling Li, Magdalena Szewczyk, David Smil, Cora Scholten, Léa Bouché, Timo Stellfeld, Cheryl Arrowsmith, Dalia Barsyte, Masoud Vedadi, Ingo Hartung, Holger Steuber, Robert Britton, Vijayaratnam Santhakumar,

ABSTRACT Protein arginine N-methyl transferase 4 (PRMT4) asymmetrically dimethylates arginine residues of histone H3 and non-histone proteins. The overexpression of PRMT4 in several cancers has stimulated interest in the discovery of inhibitors as biological tools and potentially therapeutics. While several PRMT4 inhibitors have been reported, most display poor selectivity against ... Read more >>

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Epigenetics 2.0: Special Issue on Epigenetics-Call for Papers.

Stuart J Conway, Paola Arimondo, Cheryl Arrowsmith, Jian Jin, Cheng Luo, Nicholas Meanwell, Wendy Young, Gunda Georg, Shaomeng Wang,

J Med Chem (Journal of medicinal chemistry)
[2020, 63(21):12129-12130]

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Correction: A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion.

Xiao-Chuan Cai, Tuo Zhang, Eui-Jun Kim, Ming Jiang, Ke Wang, Junyi Wang, Shi Chen, Nawei Zhang, Hong Wu, Fengling Li, Carlo C Dela Seña, Hong Zeng, Victor Vivcharuk, Xiang Niu, Weihong Zheng, Jonghan P Lee, Yuling Chen, Dalia Barsyte, Magda Szewczyk, Taraneh Hajian, Glorymar Ibáñez, Aiping Dong, Ludmila Dombrovski, Zhenyu Zhang, Haiteng Deng, Jinrong Min, Cheryl H Arrowsmith, Linas Mazutis, Lei Shi, Masoud Vedadi, Peter J Brown, Jenny Xiang, Li-Xuan Qin, Wei Xu, Minkui Luo,

Elife (eLife)
[2020, 9:]

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LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium.

Rosalie T Zwiggelaar, Håvard T Lindholm, Madeleine Fosslie, Marianne Terndrup Pedersen, Yuki Ohta, Alberto Díez-Sánchez, Mara Martín-Alonso, Jenny Ostrop, Mami Matano, Naveen Parmar, Emilie Kvaløy, Roos R Spanjers, Kamran Nazmi, Morten Rye, Finn Drabløs, Cheryl Arrowsmith, John Arne Dahl, Kim B Jensen, Toshiro Sato, Menno J Oudhoff,

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell-skewed organoid cultures. We found that lysine-specific demethylase ... Read more >>

Sci Adv (Science advances)
[2020, 6(37):]

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Identification of Lysine Isobutyrylation as A New Histone Modification Mark

Zhesi Zhu, Zhen Han, Levon Halabelian, Xiangkun Yang, Jun Ding, Nawei Zhang, Liza Ngo, Jiabao Song, Hong Zeng, Maomao He, Yingming Zhao, Cheryl Arrowsmith, Minkui Luo, Michael Bartlett, George Zheng,

Abstract Short-chain acylation of lysine residues in eukaryotic proteins are recognized as essential posttranslational chemical modifications (PTMs) that regulate cellular processes from transcription, cell cycle, metabolism, to signal transduction. Lysine butyrylation was initially discovered as a normal straight chain butyrylation (Knbu). Here we report its structural isomer, branched chain butyrylation, ... Read more >>

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A semi-automated organoid screening method demonstrates epigenetic control of intestinal epithelial maturation

Jenny Ostrop, Rosalie Zwiggelaar, Marianne Terndrup Pedersen, François Gerbe, Korbinian Bösl, Håvard Lindholm, Alberto Díez-Sánchez, Naveen Parmar, Silke Radetzki, Jens Peter von Kries, Philippe Jay, Kim Jensen, Cheryl Arrowsmith, Menno Oudhoff,

Abstract Intestinal organoids are an excellent model to study epithelial biology. Yet, the selection of analytical tools to accurately quantify heterogeneous organoid cultures remains limited. Here, we developed a semi-automated organoid screening method, which we applied to a library of highly specific chemical probes to identify epigenetic regulators of intestinal ... Read more >>

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Epigenetic Switch-Induced Viral Mimicry Evasion in Chemotherapy-Resistant Breast Cancer.

Geneviève Deblois, Seyed Ali Madani Tonekaboni, Giacomo Grillo, Constanza Martinez, Yunchi Ingrid Kao, Felicia Tai, Ilias Ettayebi, Anne-Marie Fortier, Paul Savage, Alexandra N Fedor, Xiaojing Liu, Paul Guilhamon, Evelyne Lima-Fernandes, Alex Murison, Hellen Kuasne, Wail Ba-Alawi, David W Cescon, Cheryl H Arrowsmith, Daniel D De Carvalho, Benjamin Haibe-Kains, Jason W Locasale, Morag Park, Mathieu Lupien,

Tumor progression upon treatment arises from preexisting resistant cancer cells and/or adaptation of persister cancer cells committing to an expansion phase. Here, we show that evasion from viral mimicry response allows the growth of taxane-resistant triple-negative breast cancer (TNBC). This is enabled by an epigenetic state adapted to taxane-induced metabolic ... Read more >>

Cancer Discov (Cancer discovery)
[2020, 10(9):1312-1329]

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Author Correction: Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.

Magdalena M Szewczyk, Yoshinori Ishikawa, Shawna Organ, Nozomu Sakai, Fengling Li, Levon Halabelian, Suzanne Ackloo, Amber L Couzens, Mohammad Eram, David Dilworth, Hideto Fukushi, Rachel Harding, Carlo C Dela Seña, Tsukasa Sugo, Kozo Hayashi, David McLeod, Carlos Zepeda, Ahmed Aman, Maria Sánchez-Osuna, Eric Bonneil, Shinji Takagi, Rima Al-Awar, Mike Tyers, Stephane Richard, Masayuki Takizawa, Anne-Claude Gingras, Cheryl H Arrowsmith, Masoud Vedadi, Peter J Brown, Hiroshi Nara, Dalia Barsyte-Lovejoy,

An amendment to this paper has been published and can be accessed via a link at the top of the paper. ... Read more >>

Nat Commun (Nature communications)
[2020, 11(1):2683]

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Metabolic Regulation of the Epigenome Drives Lethal Infantile Ependymoma.

Kulandaimanuvel Antony Michealraj, Sachin A Kumar, Leo J Y Kim, Florence M G Cavalli, David Przelicki, John B Wojcik, Alberto Delaidelli, Andrea Bajic, Olivier Saulnier, Graham MacLeod, Ravi N Vellanki, Maria C Vladoiu, Paul Guilhamon, Winnie Ong, John J Y Lee, Yanqing Jiang, Borja L Holgado, Alex Rasnitsyn, Ahmad A Malik, Ricky Tsai, Cory M Richman, Kyle Juraschka, Joonas Haapasalo, Evan Y Wang, Pasqualino De Antonellis, Hiromichi Suzuki, Hamza Farooq, Polina Balin, Kaitlin Kharas, Randy Van Ommeren, Olga Sirbu, Avesta Rastan, Stacey L Krumholtz, Michelle Ly, Moloud Ahmadi, Geneviève Deblois, Dilakshan Srikanthan, Betty Luu, James Loukides, Xiaochong Wu, Livia Garzia, Vijay Ramaswamy, Evgeny Kanshin, María Sánchez-Osuna, Ibrahim El-Hamamy, Fiona J Coutinho, Panagiotis Prinos, Sheila Singh, Laura K Donovan, Craig Daniels, Daniel Schramek, Mike Tyers, Samuel Weiss, Lincoln D Stein, Mathieu Lupien, Bradly G Wouters, Benjamin A Garcia, Cheryl H Arrowsmith, Poul H Sorensen, Stephane Angers, Nada Jabado, Peter B Dirks, Stephen C Mack, Sameer Agnihotri, Jeremy N Rich, Michael D Taylor,

Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of ... Read more >>

Cell (Cell)
[2020, 181(6):1329-1345.e24]

Cited: 2 times

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Discovery of a First-in-Class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor.

Yudao Shen, Fengling Li, Magdalena M Szewczyk, Levon Halabelian, Kwang-Su Park, Irene Chau, Aiping Dong, Hong Zeng, He Chen, Fanye Meng, Dalia Barsyte-Lovejoy, Cheryl H Arrowsmith, Peter J Brown, Jing Liu, Masoud Vedadi, Jian Jin,

Protein arginine methyltransferase 6 (PRMT6) plays important roles in several biological processes associated with multiple cancers. Well-characterized potent, selective, and cell-active PRMT6 inhibitors are invaluable tools for testing biological and therapeutic hypotheses. Although there are several known reversible PRMT6 inhibitors, covalent PRMT6 inhibitors have not been reported. Based on a ... Read more >>

J Med Chem (Journal of medicinal chemistry)
[2020, 63(10):5477-5487]

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LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Rosalie Zwiggelaar, Håvard Lindholm, Madeleine Fosslie, Marianne Pedersen, Yuki Ohta, Alberto Díez-Sánchez, Mara Martín-Alonso, Jenny Ostrop, Mami Matano, Naveen Parmar, Emilie Kvaløy, Roos Spanjers, Kamran Nazmi, Morten Rye, Finn Drabløs, Cheryl Arrowsmith, John Arne Dahl, Kim Jensen, Toshiro Sato, Menno Oudhoff,

ABSTRACT Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify new regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell-skewed organoid cultures. We found that ... Read more >>

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HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells.

Vipul Shukla, Levon Halabelian, Sanjana Balagere, Daniela Samaniego-Castruita, Douglas E Feldman, Cheryl H Arrowsmith, Anjana Rao, L Aravind,

Mol Cell (Molecular cell)
[2020, 77(5):1154]

Cited: 1 time

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Discovery of a chemical probe for PRDM9.

Abdellah Allali-Hassani, Magdalena M Szewczyk, Danton Ivanochko, Shawna L Organ, Jabez Bok, Jessica Sook Yuin Ho, Florence P H Gay, Fengling Li, Levi Blazer, Mohammad S Eram, Levon Halabelian, David Dilworth, Genna M Luciani, Evelyne Lima-Fernandes, Qin Wu, Peter Loppnau, Nathan Palmer, S Zakiah A Talib, Peter J Brown, Matthieu Schapira, Philipp Kaldis, Ronan C O'Hagan, Ernesto Guccione, Dalia Barsyte-Lovejoy, Cheryl H Arrowsmith, John M Sanders, Solomon D Kattar, D Jonathan Bennett, Benjamin Nicholson, Masoud Vedadi,

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 ... Read more >>

Nat Commun (Nature communications)
[2019, 10(1):5759]

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HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells.

Vipul Shukla, Levon Halabelian, Sanjana Balagere, Daniela Samaniego-Castruita, Douglas E Feldman, Cheryl H Arrowsmith, Anjana Rao, L Aravind,

HMCES (5hmC binding, embryonic stem cell-specific-protein), originally identified as a protein capable of binding 5-hydroxymethylcytosine (5hmC), an epigenetic modification generated by TET proteins, was previously reported to covalently crosslink to DNA at abasic sites via a conserved cysteine. We show here that Hmces-deficient mice display normal hematopoiesis without global alterations ... Read more >>

Mol. Cell (Molecular cell)
[2020, 77(2):384-394.e4]

Cited: 4 times

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Discovery of Small Molecule Antagonists of the USP5 Zinc Finger Ubiquitin-Binding Domain.

Mandeep K Mann, Ivan Franzoni, Renato Ferreira de Freitas, Wolfram Tempel, Scott Houliston, Leanna Smith, Masoud Vedadi, Cheryl H Arrowsmith, Rachel J Harding, Matthieu Schapira,

USP5 disassembles unanchored polyubiquitin chains to recycle free monoubiquitin, and is one of the 12 ubiquitin specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2019, 62(22):10144-10155]

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A chemical probe of CARM1 alters epigenetic plasticity against breast cancer cell invasion.

Xiao-Chuan Cai, Tuo Zhang, Eui-Jun Kim, Ming Jiang, Ke Wang, Junyi Wang, Shi Chen, Nawei Zhang, Hong Wu, Fengling Li, Carlo C Dela Seña, Hong Zeng, Victor Vivcharuk, Xiang Niu, Weihong Zheng, Jonghan P Lee, Yuling Chen, Dalia Barsyte, Magda Szewczyk, Taraneh Hajian, Glorymar Ibáñez, Aiping Dong, Ludmila Dombrovski, Zhenyu Zhang, Haiteng Deng, Jinrong Min, Cheryl H Arrowsmith, Linas Mazutis, Lei Shi, Masoud Vedadi, Peter J Brown, Jenny Xiang, Li-Xuan Qin, Wei Xu, Minkui Luo,

CARM1 is a cancer-relevant protein arginine methyltransferase that regulates many aspects of transcription. Its pharmacological inhibition is a promising anti-cancer strategy. Here SKI-73 (6a in this work) is presented as a CARM1 chemical probe with pro-drug properties. SKI-73 (6a) can rapidly penetrate cell membranes and then be processed into active ... Read more >>

Elife (eLife)
[2019, 8:]

Cited: 1 time

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A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function.

Vincent Fagan, Catrine Johansson, Carina Gileadi, Octovia Monteiro, James E Dunford, Reshma Nibhani, Martin Philpott, Jessica Malzahn, Graham Wells, Ruth Faram, Adam P Cribbs, Nadia Halidi, Fengling Li, Irene Chau, Holger Greschik, Srikannathasan Velupillai, Abdellah Allali-Hassani, James Bennett, Thomas Christott, Charline Giroud, Andrew M Lewis, Kilian V M Huber, Nick Athanasou, Chas Bountra, Manfred Jung, Roland Schüle, Masoud Vedadi, Cheryl Arrowsmith, Yan Xiong, Jian Jin, Oleg Fedorov, Gillian Farnie, Paul E Brennan, Udo Oppermann,

Modifications of histone tails, including lysine/arginine methylation, provide the basis of a "chromatin or histone code". Proteins that contain "reader" domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as ... Read more >>

J Med Chem (Journal of medicinal chemistry)
[2019, 62(20):9008-9025]

Cited: 1 time

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Targeting non-bromodomain chromatin readers.

Cheryl H Arrowsmith, Matthieu Schapira,

Chromatin regulatory proteins are increasingly recognized as potential new drug targets. Many of these proteins harbor one or more so called 'reader domains' that recognize covalent modifications of lysine and arginine residues, typically on histones, which mediate specific interactions within chromatin. Here we review recent progress in the discovery of ... Read more >>

Nat Struct Mol Biol (Nature structural & molecular biology)
[2019, 26(10):863-869]

Cited: 2 times

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GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Qin Wu, Wail ba-alawi, Genevieve Deblois, Jennifer Cruickshank, Shili Duan, Evelyne Lima-Fernandes, Jillian Haight, Seyed Ali Madani Tonekaboni, Anne-Marie Fortier, Hellen Kuasne, Trevor McKee, Hassan Mahmoud, Sarina Cameron, Nergiz Dogan-Artun, WenJun Chen, Ravi Vellanki, Stanley Zhou, Susan Done, Morag Park, David Cescon, Benjamin Haibe-Kains, Mathieu Lupien, Cheryl Arrowsmith,

Abstract Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1 ) and associated metabolic ... Read more >>

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Pervasive H3K27 Acetylation Leads to ERV Expression and a Therapeutic Vulnerability in H3K27M Gliomas.

Brian Krug, Nicolas De Jay, Ashot S Harutyunyan, Shriya Deshmukh, Dylan M Marchione, Paul Guilhamon, Kelsey C Bertrand, Leonie G Mikael, Melissa K McConechy, Carol C L Chen, Sima Khazaei, Robert F Koncar, Sameer Agnihotri, Damien Faury, Benjamin Ellezam, Alexander G Weil, Josie Ursini-Siegel, Daniel D De Carvalho, Peter B Dirks, Peter W Lewis, Paolo Salomoni, Mathieu Lupien, Cheryl Arrowsmith, Paul F Lasko, Benjamin A Garcia, Claudia L Kleinman, Nada Jabado, Stephen C Mack,

Cancer Cell (Cancer cell)
[2019, 36(3):338-339]

Cited: 1 time

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Selective, Small-Molecule Co-Factor Binding Site Inhibition of a Su(var)3-9, Enhancer of Zeste, Trithorax Domain Containing Lysine Methyltransferase.

Alexandria P Taylor, Magdalena Swewczyk, Steven Kennedy, Viacheslav V Trush, Hong Wu, Hong Zeng, Aiping Dong, Renato Ferreira de Freitas, John Tatlock, Robert A Kumpf, Martin Wythes, Agustin Casimiro-Garcia, Rajiah Aldrin Denny, Mihir D Parikh, Fengling Li, Dalia Barsyte-Lovejoy, Matthieu Schapira, Masoud Vedadi, Peter J Brown, Cheryl H Arrowsmith, Dafydd R Owen,

The first chemical probe to primarily occupy the co-factor binding site of a Su(var)3-9, enhancer of a zeste, trithorax (SET) domain containing protein lysine methyltransferase (PKMT) is reported. Protein methyltransferases require S-adenosylmethionine (SAM) as a co-factor (methyl donor) for enzymatic activity. However, SAM itself represents a poor medicinal chemistry starting ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2019, 62(17):7669-7683]

Cited: 1 time

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The MLL1 trimeric catalytic complex is a dynamic conformational ensemble stabilized by multiple weak interactions.

Lilia Kaustov, Alexander Lemak, Hong Wu, Marco Faini, Lixin Fan, Xianyang Fang, Hong Zeng, Shili Duan, Abdellah Allali-Hassani, Fengling Li, Yong Wei, Masoud Vedadi, Ruedi Aebersold, Yunxing Wang, Scott Houliston, Cheryl H Arrowsmith,

Histone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. The catalytic activity of this family is dependent on interactions with additional conserved proteins, but the ... Read more >>

Nucleic Acids Res (Nucleic acids research)
[2019, 47(17):9433-9447]

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Addendum: A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1.

Jacob I Stuckey, Bradley M Dickson, Nancy Cheng, Yanli Liu, Jacqueline L Norris, Stephanie H Cholensky, Wolfram Tempel, Su Qin, Katherine G Huber, Cari Sagum, Karynne Black, Fengling Li, Xi-Ping Huang, Bryan L Roth, Brandi M Baughman, Guillermo Senisterra, Samantha G Pattenden, Masoud Vedadi, Peter J Brown, Mark TBedford, Jinrong Min, Cheryl H Arrowsmith, Lindsey I James, Stephen V Frye,

Nat Chem Biol (Nature chemical biology)
[2019, 15(8):846]

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Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1).

Yan Xiong, Holger Greschik, Catrine Johansson, Ludwig Seifert, Johannes Bacher, Kwang-Su Park, Nicolas Babault, Michael Martini, Vincent Fagan, Fengling Li, Irene Chau, Thomas Christott, David Dilworth, Dalia Barsyte-Lovejoy, Masoud Vedadi, Cheryl H Arrowsmith, Paul Brennan, Oleg Fedorov, Manfred Jung, Gillian Farnie, Jing Liu, Udo Oppermann, Roland Schüle, Jian Jin,

By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-active SPIN1 ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2019, 62(20):8996-9007]

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