Levon Halabelian

Principal Investigator

University of Toronto
l.halabelian@utoronto.ca
+1 416 9463876

Dr. Levon Halabelian, PhD is an Assistant Professor at the Department of Pharmacology and Toxicology, UofT, and Principal Investigator in structural biology at the SGC-Toronto. His research focuses on using x-ray crystallography and chemical biology tools to uncover the structures, functions, and therapeutic potential of the human WD-repeat (WDR) domain-containing proteins, one of the largest human protein families and highly enriched in disease-associated proteins.  He is involved in structure-guided chemical probes and drug discovery efforts including the novel revolutionary PROTAC drug modality. Many of these projects are in collaboration with the pharmaceutical industry and AI-based drug-discovery groups from academia and industry. Dr. Halabelian is also the interim leader of SGC’s new open science TEP program in Women’s and Children’s Health funded by the Bill & Melinda Gates Foundation.

Research Areas

My group is interested in using the structural and chemical biology tools to uncover the structures and functions of human WD-repeat (WDR) proteins that are often associated with diverse human diseases, including neurodegenerative diseases and cancer. WDR domains comprise an emerging class of druggable protein modules and we seek to develop chemical biology tools to elucidate the function and therapeutic potential of select members of this family, such as LRRK2 and WDR41, which are associated with Parkinson’s disease and amyotrophic-lateral sclerosis (ALS), respectively. We are also interested in targeting key components of the ribosomal biogenesis pathway (WDR12, WDR55) for cancer therapy, which is becoming more attractive as promising findings emerge. Furthermore, many WDRs constitute the substrate recognition domain of E3-ligases, and we are interested in identifying small-molecule handles for the development of proteolysis-targeting chimeras (PROTACs) for targeted protein degradation. My team has also actively contributed to the characterization of other human proteins including DNA-repair proteins (HMCES), tRNA-modifying enzymes (PUS7), protein Arginine methyltransferases (PRMTs) involved in epigenetic regulation and ubiquitin-specific proteases (USP9X).

A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6.
Shen Y, Li F, Szewczyk MM, Halabelian L, Chau I, Eram MS, Dela Seña C, Park KS, Meng F, Chen H, Zeng H, McLeod D, Zepeda-Velázquez CA, Campbell RM, Mader MM, Watson BM, Schapira M, Arrowsmith CH, Al-Awar R, Barsyte-Lovejoy D, Kaniskan HÜ, Brown PJ, Vedadi M, Jin J
J Med Chem. 2021 . doi: 10.1021/acs.jmedchem.0c02160
PMID: 33591753

Identification of lysine isobutyrylation as a new histone modification mark.
Zhu Z, Han Z, Halabelian L, Yang X, Ding J, Zhang N, Ngo L, Song J, Zeng H, He M, Zhao Y, Arrowsmith CH, Luo M, Bartlett MG, Zheng YG
Nucleic Acids Res. 2020 . doi: 10.1093/nar/gkaa1176
PMID: 33313896

Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.
Szewczyk MM, Ishikawa Y, Organ S, Sakai N, Li F, Halabelian L, Ackloo S, Couzens AL, Eram M, Dilworth D, Fukushi H, Harding R, Dela Seña CC, Sugo T, Hayashi K, McLeod D, Zepeda C, Aman A, Sánchez-Osuna M, Bonneil E, Takagi S, Al-Awar R, Tyers M, Richard S, Takizawa M, Gingras AC, Arrowsmith CH, Vedadi M, Brown PJ, Nara H, Barsyte-Lovejoy D
Nat Commun. 2020 11(1):2396. doi: 10.1038/s41467-020-16271-z
PMID: 32409666

Discovery of a First-in-class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor.
Shen Y, Li F, Szewczyk MM, Halabelian L, Park KS, Chau I, Dong A, Zeng H, Chen H, Meng F, Barsyte-Lovejoy D, Arrowsmith CH, Brown P, Liu J, Vedadi M, Jin J
J. Med. Chem.. 2020 . doi: 10.1021/acs.jmedchem.0c00406
PMID: 32367723

Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition.
Halabelian L, Ravichandran M, Li Y, Zeng H, Rao A, Aravind L, Arrowsmith CH
Nat. Struct. Mol. Biol.. 2019 . doi: 10.1038/s41594-019-0246-6
PMID: 31235913

HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells.
Shukla V, Halabelian L, Balagere S, Samaniego-Castruita D, Feldman DE, Arrowsmith CH, Rao A, Aravind L
Mol. Cell. 2019 . doi: 10.1016/j.molcel.2019.10.031
PMID: 31806351

Discovery of a chemical probe for PRDM9.
Allali-Hassani A, Szewczyk MM, Ivanochko D, Organ SL, Bok J, Ho JSY, Gay FPH, Li F, Blazer L, Eram MS, Halabelian L, Dilworth D, Luciani GM, Lima-Fernandes E, Wu Q, Loppnau P, Palmer N, Talib SZA, Brown PJ, Schapira M, Kaldis P, O'Hagan RC, Guccione E, Barsyte-Lovejoy D, Arrowsmith CH, Sanders JM, Kattar SD, Bennett DJ, Nicholson B, Vedadi M
Nat Commun. 2019 10(1):5759. doi: 10.1038/s41467-019-13652-x
PMID: 31848333

The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.
Jakobsson ME, Małecki JM, Halabelian L, Nilges BS, Pinto R, Kudithipudi S, Munk S, Davydova E, Zuhairi FR, Arrowsmith CH, Jeltsch A, Leidel SA, Olsen JV, Falnes PØ
Nat Commun. 2018 9(1):3411. doi: 10.1038/s41467-018-05646-y
PMID: 30143613

Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex.
Ivanochko D, Halabelian L, Henderson E, Savitsky P, Jain H, Marcon E, Duan S, Hutchinson A, Seitova A, Barsyte-Lovejoy D, Filippakopoulos P, Greenblatt J, Lima-Fernandes E, Arrowsmith CH
Nucleic Acids Res.. 2018 . doi: 10.1093/nar/gky1192
PMID: 30462309

2024

Loss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing.
Shen L, Ma X, Wang Y, Wang Z, Zhang Y, Pham HQH, Tao X, Cui Y, Wei J, Lin D, Abeywanada T, Hardikar S, Halabelian L, Smith N, Chen T, Barsyte-Lovejoy D, Qiu S, Xing Y, Yang Y
Nat Commun. 01.04.2024 15(1):2809. doi: 10.1038/s41467-024-47107-9
PMID: 38561334

Big data and benchmarking initiatives to bridge the gap from AlphaFold to drug design.
Schapira M, Halabelian L, Arrowsmith CH, Harding RJ
Nat Chem Biol. 08.03.2024 . doi: 10.1038/s41589-024-01570-z
PMID: 38459278

Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials.
Gilleran JA, Ashraf K, Delvillar M, Eck T, Fondekar R, Miller EB, Hutchinson A, Dong A, Seitova A, De Souza ML, Augeri D, Halabelian L, Siekierka J, Rotella DP, Gordon J, Childers WE, Grier MC, Staker BL, Roberge JY, Bhanot P
J Med Chem. 19.02.2024 . doi: 10.1021/acs.jmedchem.3c01795
PMID: 38372781

ChemRAP uncovers specific mRNA translation regulation via RNA 5' phospho-methylation.
Ipas H, Gouws EB, Abell NS, Chiou PC, Devanathan SK, Hervé S, Lee S, Mercado M, Reinsborough C, Halabelian L, Arrowsmith CH, Xhemalçe B
EMBO Rep. 23.01.2024 . doi: 10.1038/s44319-024-00059-z
PMID: 38263329

2023

The co-crystal structure of Cbl-b and a small-molecule inhibitor reveals the mechanism of Cbl-b inhibition.
Kimani SW, Perveen S, Szewezyk M, Zeng H, Dong A, Li F, Ghiabi P, Li Y, Chau I, Arrowsmith CH, Barsyte-Lovejoy D, Santhakumar V, Vedadi M, Halabelian L
Commun Biol. 16.12.2023 6(1):1272. doi: 10.1038/s42003-023-05655-8
PMID: 38104184

Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning.
Ahmad S, Xu J, Feng JA, Hutchinson A, Zeng H, Ghiabi P, Dong A, Centrella PA, Clark MA, Guié MA, Guilinger JP, Keefe AD, Zhang Y, Cerruti T, Cuozzo JW, von Rechenberg M, Bolotokova A, Li Y, Loppnau P, Seitova A, Li YY, Santhakumar V, Brown PJ, Ackloo S, Halabelian L
J Med Chem. 23.11.2023 . doi: 10.1021/acs.jmedchem.3c01471
PMID: 37996079

Discovery of a 53BP1 Small Molecule Antagonist Using a Focused DNA-Encoded Library Screen.
Shell DJ, Foley CA, Wang Q, Smith CM, Guduru SKR, Zeng H, Dong A, Norris-Drouin JL, Axtman M, Hardy PB, Gupta G, Halabelian L, Frye SV, James LI, Pearce KH
J Med Chem. 02.10.2023 . doi: 10.1021/acs.jmedchem.3c01192
PMID: 37782247

Discovery of a Novel DCAF1 Ligand Using a Drug-Target Interaction Prediction Model: Generalizing Machine Learning to New Drug Targets.
Kimani SW, Owen J, Green SR, Li F, Li Y, Dong A, Brown PJ, Ackloo S, Kuter D, Yang C, MacAskill M, MacKinnon SS, Arrowsmith CH, Schapira M, Shahani V, Halabelian L
J Chem Inf Model. 23.06.2023 . doi: 10.1021/acs.jcim.3c00082
PMID: 37350740

Discovery of Nanomolar DCAF1 Small Molecule Ligands.
Li ASM, Kimani S, Wilson B, Noureldin M, González-Álvarez H, Mamai A, Hoffer L, Guilinger JP, Zhang Y, von Rechenberg M, Disch JS, Mulhern CJ, Slakman BL, Cuozzo JW, Dong A, Poda G, Mohammed M, Saraon P, Mittal M, Modh P, Rathod V, Patel B, Ackloo S, Santhakumar V, Szewczyk MM, Barsyte-Lovejoy D, Arrowsmith CH, Marcellus R, Guié MA, Keefe AD, Brown PJ, Halabelian L, Al-Awar R, Vedadi M
J Med Chem. 22.03.2023 . doi: 10.1021/acs.jmedchem.2c02132
PMID: 36948210

2022

Structure and activity of human TMPRSS2 protease implicated in SARS-CoV-2 activation.
Fraser BJ, Beldar S, Seitova A, Hutchinson A, Mannar D, Li Y, Kwon D, Tan R, Wilson RP, Leopold K, Subramaniam S, Halabelian L, Arrowsmith CH, Bénard F
Nat Chem Biol. 08.06.2022 . doi: 10.1038/s41589-022-01059-7
PMID: 35676539

2021

Histone lysine methacrylation is a dynamic post-translational modification regulated by HAT1 and SIRT2.
Delaney K, Tan M, Zhu Z, Gao J, Dai L, Kim S, Ding J, He M, Halabelian L, Yang L, Nagarajan P, Parthun MR, Lee S, Khochbin S, Zheng YG, Zhao Y
Cell Discov. 28.12.2021 7(1):122. doi: 10.1038/s41421-021-00344-4
PMID: 34961760

The human pseudouridine synthase PUS7 recognizes RNA with an extended multi-domain binding surface.
Guegueniat J, Halabelian L, Zeng H, Dong A, Li Y, Wu H, Arrowsmith CH, Kothe U
Nucleic Acids Res. 28.10.2021 . doi: 10.1093/nar/gkab934
PMID: 34718722

Chemical Genetics Screen Identifies COPB2 Tool Compounds That Alters ER Stress Response and Induces RTK Dysregulation in Lung Cancer Cells.
Saraon P, Snider J, Schormann W, Rai A, Radulovich N, Sánchez-Osuna M, Coulombe-Huntington J, Huard C, Mohammed M, Lima-Fernandes E, Thériault B, Halabelian L, Chan M, Joshi D, Drecun L, Yao Z, Pathmanathan S, Wong V, Lyakisheva A, Aboualizadeh F, Niu L, Li F, Kiyota T, Subramanian R, Joseph B, Aman A, Prakesch M, Isaac M, Mamai A, Poda G, Vedadi M, Marcellus R, Uehling D, Leighl N, Sacher A, Samaržija M, Jakopović M, Arrowsmith C, Tyers M, Tsao MS, Andrews D, Al-Awar R, Stagljar I
J Mol Biol. 16.10.2021 433(23):167294. doi: 10.1016/j.jmb.2021.167294
PMID: 34662547

Structure and Function of Protein Arginine Methyltransferase PRMT7.
Halabelian L, Barsyte-Lovejoy D
Life (Basel). 30.07.2021 11(8):. doi: 10.3390/life11080768
PMID: 34440512

Development of LM98, a Small-Molecule TEAD Inhibitor Derived from Flufenamic Acid.
Gagnon A, Mélin L, Abdullayev S, Fnaiche A, Vu V, Gonzalez Suarez N, Zeng H, Szewczyk M, Li F, Sinisterra G, Allali-Hassani A, Chau I, Dong A, Woo S, Annabi B, Halabelian L, LaPlante S, Vedadi M, Barsyte-Lovejoy D, Santhakumar V
ChemMedChem. 23.06.2021 . doi: 10.1002/cmdc.202100432
PMID: 34164919

Affinity-matured HLA class II dimers for robust staining of antigen-specific CD4+ T cells.
Sugata K, Matsunaga Y, Yamashita Y, Nakatsugawa M, Guo T, Halabelian L, Ohashi Y, Saso K, Rahman MA, Anczurowski M, Wang CH, Murata K, Saijo H, Kagoya Y, Ly D, Burt BD, Butler MO, Mak TW, Hirano N
Nat Biotechnol. 01.03.2021 . doi: 10.1038/s41587-021-00836-4
PMID: 33649568

A First-in-Class, Highly Selective and Cell-Active Allosteric Inhibitor of Protein Arginine Methyltransferase 6.
Shen Y, Li F, Szewczyk MM, Halabelian L, Chau I, Eram MS, Dela Seña C, Park KS, Meng F, Chen H, Zeng H, McLeod D, Zepeda-Velázquez CA, Campbell RM, Mader MM, Watson BM, Schapira M, Arrowsmith CH, Al-Awar R, Barsyte-Lovejoy D, Kaniskan HÜ, Brown PJ, Vedadi M, Jin J
J Med Chem. 16.02.2021 . doi: 10.1021/acs.jmedchem.0c02160
PMID: 33591753

2020

Identification of lysine isobutyrylation as a new histone modification mark.
Zhu Z, Han Z, Halabelian L, Yang X, Ding J, Zhang N, Ngo L, Song J, Zeng H, He M, Zhao Y, Arrowsmith CH, Luo M, Bartlett MG, Zheng YG
Nucleic Acids Res. 11.12.2020 . doi: 10.1093/nar/gkaa1176
PMID: 33313896

Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response.
Szewczyk MM, Ishikawa Y, Organ S, Sakai N, Li F, Halabelian L, Ackloo S, Couzens AL, Eram M, Dilworth D, Fukushi H, Harding R, Dela Seña CC, Sugo T, Hayashi K, McLeod D, Zepeda C, Aman A, Sánchez-Osuna M, Bonneil E, Takagi S, Al-Awar R, Tyers M, Richard S, Takizawa M, Gingras AC, Arrowsmith CH, Vedadi M, Brown PJ, Nara H, Barsyte-Lovejoy D
Nat Commun. 14.05.2020 11(1):2396. doi: 10.1038/s41467-020-16271-z
PMID: 32409666

Discovery of a First-in-class Protein Arginine Methyltransferase 6 (PRMT6) Covalent Inhibitor.
Shen Y, Li F, Szewczyk MM, Halabelian L, Park KS, Chau I, Dong A, Zeng H, Chen H, Meng F, Barsyte-Lovejoy D, Arrowsmith CH, Brown P, Liu J, Vedadi M, Jin J
J. Med. Chem.. 05.05.2020 . doi: 10.1021/acs.jmedchem.0c00406
PMID: 32367723

2019

Discovery of a chemical probe for PRDM9.
Allali-Hassani A, Szewczyk MM, Ivanochko D, Organ SL, Bok J, Ho JSY, Gay FPH, Li F, Blazer L, Eram MS, Halabelian L, Dilworth D, Luciani GM, Lima-Fernandes E, Wu Q, Loppnau P, Palmer N, Talib SZA, Brown PJ, Schapira M, Kaldis P, O'Hagan RC, Guccione E, Barsyte-Lovejoy D, Arrowsmith CH, Sanders JM, Kattar SD, Bennett DJ, Nicholson B, Vedadi M
Nat Commun. 17.12.2019 10(1):5759. doi: 10.1038/s41467-019-13652-x
PMID: 31848333

HMCES Functions in the Alternative End-Joining Pathway of the DNA DSB Repair during Class Switch Recombination in B Cells.
Shukla V, Halabelian L, Balagere S, Samaniego-Castruita D, Feldman DE, Arrowsmith CH, Rao A, Aravind L
Mol. Cell. 15.11.2019 . doi: 10.1016/j.molcel.2019.10.031
PMID: 31806351

The C-Terminal Domains SnRK2 Box and ABA Box Have a Role in Sugarcane SnRK2s Auto-Activation and Activity.
Righetto GL, Sriranganadane D, Halabelian L, Chiodi CG, Elkins JM, Massirer KB, Gileadi O, Menossi M, Couñago RM
Front Plant Sci. 18.10.2019 10:1105. doi: 10.3389/fpls.2019.01105
PMID: 31620147

The C-Terminal Domains SnRK2 Box and ABA Box Have a Role in Sugarcane SnRK2s Auto-Activation and Activity
Righetto GL, Sriranganadane D, Halabelian L, Chiodi CG, Elkins JM, Massirer KB, Gileadi O, Menossi M, Couñago RM
Frontiers in Plant Science. 16.09.2019 10:1105-. doi: 10.3389/fpls.2019.01105
PMID: 31620147

Structural basis of HMCES interactions with abasic DNA and multivalent substrate recognition.
Halabelian L, Ravichandran M, Li Y, Zeng H, Rao A, Aravind L, Arrowsmith CH
Nat. Struct. Mol. Biol.. 24.06.2019 . doi: 10.1038/s41594-019-0246-6
PMID: 31235913

2018

Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex.
Ivanochko D, Halabelian L, Henderson E, Savitsky P, Jain H, Marcon E, Duan S, Hutchinson A, Seitova A, Barsyte-Lovejoy D, Filippakopoulos P, Greenblatt J, Lima-Fernandes E, Arrowsmith CH
Nucleic Acids Res.. 20.11.2018 . doi: 10.1093/nar/gky1192
PMID: 30462309

Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex.
Ivanochko, D; Halabelian, L; Henderson, E; Savitsky, P; Jain, H; Marcon, E; Duan, S; Hutchinson, A; Seitova, A; Barsyte-Lovejoy, D; Filippakopoulos, P; Greenblatt, J; Lima-Fernandes, E; Arrowsmith, CH;
Nucleic Acids Research. 20.11.2018 :-. doi: 10.1093/nar/gky1192
PMID: 30462309

The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates.
Jakobsson ME, Małecki JM, Halabelian L, Nilges BS, Pinto R, Kudithipudi S, Munk S, Davydova E, Zuhairi FR, Arrowsmith CH, Jeltsch A, Leidel SA, Olsen JV, Falnes PØ
Nat Commun. 24.08.2018 9(1):3411. doi: 10.1038/s41467-018-05646-y
PMID: 30143613

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