PhD, University of Toronto
At A Glance
- We are an interdisciplinary lab studying the structure, function and chemical modulation of proteins involved in epigenetics and nuclear signalling – cellular mechanisms that are disrupted in cancer and other diseases.
- We use structural biology and chemical biology approaches to understand how transcriptional and chromatin regulatory proteins recognize, interact with and signal to other molecular components of the cell.
- In conjunction with the Structural Genomics Consortium (SGC), we are using our protein structural information to develop new chemical genetic tools to define, perturb and manipulate essential functions of proteins involved in methylation dependent signalling.
Dr. Arrowsmith received her Ph.D. in chemistry from the University of Toronto and carried out postdoctoral research at Stanford University. She is the director of the Toronto Node of the Structural Genomics Consortium (SGC), Senior Scientist at the Princess Margaret Cancer Centre, and Professor of Medical Biophysics at the University of Toronto. Dr. Arrowsmith is an internationally recognized expert in cancer related structural biology & chemical biology and epigenetics. She has been the leader of the Toronto site of the SGC since its inception and coordinates the SGC’s epigenetic chemical probe program. Dr. Arrowsmith was co-founder of Affinium Pharmaceuticals, a structure-based biotech that developed an anti-MRSA antibiotic that recently completed successful phase IIa trials. She has served as a member of 18 scientific advisory boards, grant review panels and journal editorial boards since 2000, including current membership on the Board of Directors of Academic Drug Discovery Consortium (ADDC). Dr. Arrowsmith holds a Canada Research Chair in Structural Genomics at the University of Toronto, has published over 250 peer reviewed articles, with more than 60 of these published in the last 5 years, and is co-author of over 1800 3D protein structures in the Protein DataBank (PDB). Her current research focuses on structural biology and chemical biology approaches to understand how transcriptional and chromatin regulatory proteins recognize, interact with and signal to other molecular components of the cell.
We have made extensive contributions to the understanding of the structure and function of important human chromatin regulatory proteins that are key modulators of disease and/or potential therapeutic targets including, p53, USP7, WDR5, HDAC7, UHRF1, and EZH2.
Using our structural and biochemical expertise, we have developed a series of chemical probes (drug-like tool compounds) targeting epigenetic regulators that are being used widely by the research community to better understand human biology and disease, and to identify new therapeutic opportunities.
We recently developed a novel inhibitor of protein-protein interaction site of WDR5, a key component of several important chromatin regulatory complexes. This chemical probes was used to demonstrate that antagonism of WDR5 protein-protein interactions results in suppression of cell growth and viability in CEBPa mutant leukemia and in breast cancer cell lines with gain of function mutations in p53.
- Grebien F, Vedadi M, Getlik M, Giambruno R, Grover A, Avellino R, Skucha A, Vittori S, Kuznetsova E, Smil D, Barsyte-Lovejoy D, Li F, Poda G, Schapira M, Wu H, Dong A, Senisterra G, Stukalov A, Huber KV, Schönegger A, Marcellus R, Bilban M, Bock C, Brown PJ, Zuber J, Bennett KL, Al-Awar R, Delwel R, Nerlov C, Arrowsmith CH, Superti-Furga G. Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia, Nat Chem Biol 11(10):815. (2015).
- Edwards AM, Arrowsmith CH, Bountra C, Bunnage ME, Feldmann M, Knight JC, Patel DD, Prinos P, Taylor MD, Sundström M, ; SGC Open Source Target-Discovery Partnership Preclinical target validation using patient-derived cells, Nat Rev Drug Discov 14(3):149-50 (2015).
- Tardat M, Albert M, Kunzmann R, Liu Z, Kaustov L, Thierry R, Duan S, Brykczynska U, Arrowsmith CH, Peters AH. Cbx2 Targets PRC1 to Constitutive Heterochromatin in Mouse Zygotes in a Parent-of-Origin-Dependent Manner. Mol Cell 58(1):157-71 (2015).
- Shah MA, Denton EL, Arrowsmith CH, Lupien M, Schapira M. A global assessment of cancer genomic alterations in epigenetic mechanisms. Epigenetics Chromatin 7(1):29 (2014).
- Barsyte-Lovejoy D, Li F, Oudhoff MJ, Tatlock JH, Dong A, Zeng H, Wu H, Freeman SA, Schapira M, Senisterra GA, Kuznetsova E, Marcellus R, Allali-Hassani A, Kennedy S, Lambert JP, Couzens AL, Aman A, Gingras AC, Al-Awar R, Fish PV, Gerstenberger BS, Roberts L, Benn CL, Grimley RL, Braam MJ, Rossi FM, Sudol M, Brown PJ, Bunnage ME, Owen DR, Zaph C, Vedadi M, Arrowsmith CH. (R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells. Proc Natl Acad Sci U S A 111(35):12853-8 (2014).
- Gelato KA, Tauber M, Ong MS, Winter S, Hiragami-Hamada K, Sindlinger J, Lemak A, Bultsma Y, Houliston S, Schwarzer D, Divecha N, Arrowsmith CH, Fischle W. Accessibility of different histone H3-binding domains of UHRF1 is allosterically regulated by phosphatidylinositol 5-phosphate. Mol Cell 54(6):905-19 (2014).
- Lemak A, Wu B, Yee A, Houliston S, Lee HW, Gutmanas A, Fang X, Garcia M, Semesi A, Wang YX, Prestegard JH, Arrowsmith CH. Structural characterization of a flexible two-domain protein in solution using small angle X-ray scattering and NMR data. Structure 22(12):1862-74 (2014).
- Senisterra G, Wu H, Allali-Hassani A, Wasney GA, Barsyte-Lovejoy D, Dombrovski L, Dong A, Nguyen KT, Smil D, Bolshan Y, Hajian T, He H, Seitova A, Chau I, Li F, Poda G, Couture JF, Brown PJ, Al-Awar R, Schapira M, Arrowsmith CH, Vedadi M. Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5. Biochem J 449(1):151-9 (2013).
- James LI, Barsyte-Lovejoy D, Zhong N, Krichevsky L, Korboukh VK, Herold JM, MacNevin CJ, Norris JL, Sagum CA, Tempel W, Marcon E, Guo H, Gao C, Huang XP, Duan S, Emili A, Greenblatt JF, Kireev DB, Jin J, Janzen WP, Brown PJ, Bedford MT, Arrowsmith CH, Frye SV. Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain. Nat Chem Biol 9(3):184-91 (2013).
- Rothbart SB, Krajewski K, Nady N, Tempel W, Xue S, Badeaux AI, Barsyte-Lovejoy D, Martinez JY, Bedford MT, Fuchs SM, Arrowsmith CH, Strahl BD. Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. Nat Struct Mol Biol 19(11):1155-60 (2012).
- Nady N, Krichevsky L, Zhong N, Duan S, Tempel W, Amaya MF, Ravichandran M, Arrowsmith CH. Histone recognition by human malignant brain tumor domains. J Mol Biol 423(5):702-18 (2012).
- Yu W, Chory EJ, Wernimont AK, Tempel W, Scopton A, Federation A, Marineau JJ, Qi J, Barsyte-Lovejoy D, Yi J, Marcellus R, Iacob RE, Engen JR, Griffin C, Aman A, Wienholds E, Li F, Pineda J, Estiu G, Shatseva T, Hajian T, Al-Awar R, Dick JE, Vedadi M, Brown PJ, Arrowsmith CH, Bradner JE, Schapira M. Catalytic site remodelling of the DOT1L methyltransferase by selective inhibitors. Nat Commun 3:1288 (2012).
- Kaustov L, Ouyang H, Amaya M, Lemak A, Nady N, Duan S, Wasney G, Vedadi M, Shapira M, Min J, Arrowsmith C. Recognition and specificity determinants of the human Cbx chromodomains, J Biol Chem 286(1):521-9 (2011).
- Lemak A, Gutmanas A, Chitayat S, Karra M, Farès C, Sunnerhagen M, Arrowsmith CH. A novel strategy for NMR resonance assignment and structure determination. J Biomol NMR 49(1):27-38 (2011).
- Nady N, Lemak A, Walker JR, Avvakumov GV, Kareta MS, Achour M, Xue S, Duan S, Allali-Hassani A, Zuo X, Wang YX, Bronner C, Chédin F, Arrowsmith CH, Dhe-Paganon S. Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. J Biol Chem 286(27):24300-11 (2011).
- Vedadi M, Barsyte-Lovejoy D, Liu F, Rival-Gervier S, Allali-Hassani A, Wigle TJ, DiMaggio PA, Wasney GA, Siarheyeva A, Dong A, Tempel W, Chen X, Chau I, Mangano TJ, Evans JM, Simpson CD, Pattenden SG, Norris JL, Kireev DB, Tripathy A, Edwards A, Roth BL, Janzen WP, Garcia BA, Ellis J, Brown PJ, Frye SV, Arrowsmith CH, Jin J. UNC0638: Potent, Selective, and Cell-penetrant Chemical Probe of Protein Lysine Methyltransferases G9a and GLP. Nature Chem Biol 7(8):566 (2011).
(Highlighted by News and Views: Nature Chemical Biology, 2011, 7, 499-500; SciBX, 2011, 4(31), doi:10.1038/scibx.2011.890)
- Schuetz A, Min J, Allali-Hassani A, Schapira M, Shuen M, Loppnau P, Mazitschek R, Kwiatkowski NP, Lewis TA, Maglathin RL, McLean TH, Bochkarev A, Plotnikov AN, Vedadi M, Arrowsmith CH. Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity. J Biol Chem 283(17):11355-63 (2008).
- Nady N, Min J, Kareta MS, Chédin F, Arrowsmith CH. A SPOT on the chromatin landscape? Histone peptide arrays as a tool for epigenetic research. Trends Biochem Sci 33(7):305-13 (2008).
- Sheng Y, Laister RC, Lemak A, Wu B, Tai E, Duan S, Lukin J, Sunnerhagen M, Srisailam S, Karra M, Benchimol S, Arrowsmith CH. Molecular Basis of Pirh2-mediated p53 ubiquitylation. Nat Struct Mol Biol 15(12):1334-42 (2008).
- Avvakumov GV, Walker JR, Xue S, Li Y, Duan S, Bronner C, Arrowsmith CH, Dhe-Paganon S. Structural basis for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature 455(7214):822-5 (2008).
- Min J, Allali-Hassani A, Nady N, Qi C, Ouyang H, Liu Y, MacKenzie F, Vedadi M, Arrowsmith CH. L3MBTL1 recognition of mono- and dimethylated histones. Nat Struct Mol Biol 14(12):1229-30 (2007).
- Sheng Y, Saridakis V. Sarkari F, Duan S, Wu T, Arrowsmith CH, and Frappier L. Molecular recognition of p53 and MDM2 by USP7/HAUSP. Nat Struct Mol Biol 13(3):285-91 (2006).
- Schuetz A, Allali-Hassani A, Martin F, Loppnau P, Vedadi M, Bochkarev A, Plotnikov AN, Arrowsmith CH and Min JR. Structural Basis for Selective Binding of WDR5 to Histone H3 Dimethylated at Lysine 4. EMBO J (25)18:4245-52 (2006).
- Saridakis V, Sheng Y, Sarkari F, Holowaty MN, Shire K, Nguyen T, Zhang RG, Liao J, Lee W, Edwards AM, Arrowsmith CH and Frappier L. Structure of the p53-binding domain of HAUSP/USP7 bound to Epstein-Barr Nuclear Antigen 1 Implications for EBV-mediated immortalization. Mol Cell 18(1):25-36 (2005).
- Bochkareva E, Kaustov L, Ayed A, Yi GS, Lu Y, Pineda-Lucena A, Liao JC, Okorokov AL, Milner J, Arrowsmith CH, Bochkarev A. Single stranded DNA mimicry in the p53 transactivation domain interaction with RPA. Proc Natl Acad Sci 102(43):15412-7 (2005).
- Chang YX, Pineda-Lucena A, Wu B, Semesi A, Le B, Ramelot T, Lee GM, Bhattacharyya S, Gutierrez P, Denisov A, Lee C-H, Cort JR, Kozlov G, Liao J, Finak G, Chen L, Wishart D, Lee W, McIntosh LP, Gehring K, Kennedy MA, Edwards AM, Arrowsmith CH. An NMR Approach for Structural Proteomics. PNAS 99:1825-30 (2002).
- Christendat D, Yee A, Dharamsi A, Kluger Y, Gerstein M, Arrowsmith CH, Edwards AM. Structural Proteomics: Prospects for High Throughput Sample Preparation. Prog Biophys Mol Biol 73, 339-345 (2000).
Helen Loo (co-supervised with Daniel De Carvalho)
Shengrui Feng (co-supervised with Daniel De Carvalho)