Rachel Harding

Rachel Harding

SGC Toronto

Harding

Biography

Dr. Rachel Harding is an Assistant Professor in the Leslie Dan Faculty of Pharmacy at the University of Toronto and a Principal Investigator at the Structural Genomics Consortium (SGC) at University Health Network (UHN). She is cross-appointed to the University of Toronto Department of Pharmacology and Toxicology and is an Affiliate Scientist at the Princess Margaret Cancer Centre. Dr. Harding completed her undergraduate degree (MBiochem) and DPhil at the University of Oxford, where she trained with Dr. Susan Lea, before moving to Toronto for postdoctoral research with Dr. Cheryl Arrowsmith at the SGC. Her postdoctoral work focused on the structure-function of Huntingtin, the protein mutated in Huntington’s disease, supported by a Huntington’s Disease Society of America Berman-Topper Family Career Development Fellowship. Dr. Harding has authored more than 40 peer-reviewed publications and, as an independent investigator, has secured more than $6 million CAD in research funding as Principal Investigator. Her research contributions have been recognised through several awards and honours, including the 2024 Hereditary Disease Foundation Nancy S. Wexler Young Investigator Prize and the 2025 Huntington Society of Canada Michael Wright Community Leadership Award.

Research Areas

The Harding laboratory uses structural biology, protein biochemistry, biophysics and chemical biology to investigate challenging and understudied areas of human biology and disease, particularly where limited molecular understanding or a lack of high-quality chemical tools has constrained therapeutic discovery. The group combines mechanistic studies with ligand discovery and chemical tool development to understand protein function and identify new opportunities for therapeutic intervention. A major focus of the laboratory is repeat expansion disorders, including Huntington’s disease and other polyglutamine diseases. The team studies how disease-associated mutations alter protein structure, interactions, dynamics and biomolecular condensation, and develops chemical tools to interrogate these processes. The laboratory also works on emerging therapeutic targets beyond neurodegeneration, including targets for non-hormonal contraception. Across these research areas, the group aims to develop robust molecular understanding, high-quality chemical tools and openly available datasets and reagents that enable both fundamental discovery and early-stage drug development.

2025

Synthesis and functional screening of novel inhibitors targeting the HDAC6 zinc finger ubiquitin-binding domain.

Geurs S, Staessens E, Bredael K, Borghgraef S, De Ridder J, Persoons L, De Jonghe S, Schols D, Mann MK, Harding RJ, Franceus J, Desmet T, Van Hecke K, Clarisse D, De Bosscher K, D'hooghe M

Eur J Med Chem. 2025-1-18 . 285:117208 .doi: 10.1016/j.ejmech.2024.117208

PMID: 39823806

2024

CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

Li F, Ackloo S, Arrowsmith CH, Ban F, Barden CJ, Beck H, Beránek J, Berenger F, Bolotokova A, Bret G, Breznik M, Carosati E, Chau I, Chen Y, Cherkasov A, Corte DD, Denzinger K, Dong A, Draga S, Dunn I, Edfeldt K, Edwards A, Eguida M, Eisenhuth P, Friedrich L, Fuerll A, Gardiner SS, Gentile F, Ghiabi P, Gibson E, Glavatskikh M, Gorgulla C, Guenther J, Gunnarsson A, Gusev F, Gutkin E, Halabelian L, Harding RJ, Hillisch A, Hoffer L, Hogner A, Houliston S, Irwin JJ, Isayev O, Ivanova A, Jacquemard C, Jarrett AJ, Jensen JH, Kireev D, Kleber J, Koby SB, Koes D, Kumar A, Kurnikova MG, Kutlushina A, Lessel U, Liessmann F, Liu S, Lu W, Meiler J, Mettu A, Minibaeva G, Moretti R, Morris CJ, Narangoda C, Noonan T, Obendorf L, Pach S, Pandit A, Perveen S, Poda G, Polishchuk P, Puls K, Pütter V, Rognan D, Roskams-Edris D, Schindler C, Sindt F, Spiwok V, Steinmann C, Stevens RL, Talagayev V, Tingey D, Vu O, Walters WP, Wang X, Wang Z, Wolber G, Wolf CA, Wortmann L, Zeng H, Zepeda CA, Zhang KYJ, Zhang J, Zheng S, Schapira M

J Chem Inf Model. 2024-11-5 . .doi: 10.1021/acs.jcim.4c01267

PMID: 39499532

Poly ADP-ribose signaling is dysregulated in Huntington disease.

Maiuri T, Bazan CB, Harding RJ, Begeja N, Kam TI, Byrne LM, Rodrigues FB, Warner MM, Neuman K, Mansoor M, Badiee M, Dasovich M, Wang K, Thompson LM, Leung AKL, Andres SN, Wild EJ, Dawson TM, Dawson VL, Arrowsmith CH, Truant R

Proc Natl Acad Sci U S A. 2024-9-27 . 121(40):e2318098121 .doi: 10.1073/pnas.2318098121

PMID: 39331414

A guide to selecting high-performing antibodies for Huntingtin (UniProt ID: P42858) for use in western blot, immunoprecipitation, and immunofluorescence.

Fanti R, Ayoubi R, Alende C, Fotouhi M, González Bolívar S, Chandrasekaran R, Southern K, Edwards AM, Harding RJ, Laflamme C

F1000Res. 2024-9-11 . 13:922 .doi: 10.12688/f1000research.153670.1

PMID: 39257448

Autoinhibition of ubiquitin-specific protease 8: insights into domain interactions and mechanisms of regulation.

Caba C, Black M, Liu Y, DaDalt AA, Mallare J, Fan L, Harding RJ, Wang Y, Vacratsis PO, Huang R, Zhuang Z, Tong Y

J Biol Chem. 2024-8-28 . 107727 .doi: 10.1016/j.jbc.2024.107727

PMID: 39214302

Huntingtin is an RNA binding protein and participates in NEAT1-mediated paraspeckles.

Yadav M, Harding RJ, Li T, Xu X, Gall-Duncan T, Khan M, Bardile CF, Sequiera GL, Duan S, Chandrasekaran R, Pan A, Bu J, Yamazaki T, Hirose T, Prinos P, Tippett L, Turner C, Curtis MA, Faull RLM, Pouladi MA, Pearson CE, He HH, Arrowsmith CH

Sci Adv. 2024-7-19 . 10(29):eado5264 .doi: 10.1126/sciadv.ado5264

PMID: 39028820

Subpocket Similarity-Based Hit Identification for Challenging Targets: Application to the WDR Domain of LRRK2.

Eguida M, Bret G, Sindt F, Li F, Chau I, Ackloo S, Arrowsmith C, Bolotokova A, Ghiabi P, Gibson E, Halabelian L, Houliston S, Harding RJ, Hutchinson A, Loppnau P, Perveen S, Seitova A, Zeng H, Schapira M, Rognan D

J Chem Inf Model. 2024-6-25 . .doi: 10.1021/acs.jcim.4c00601

PMID: 38916159

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. 2024-3-8 . .doi: 10.1038/s41589-024-01570-z

PMID: 38459278

Small Molecule Screen Identifies Non-catalytic USP3 Chemical Handle.

Mann MK, Wolf E, Silva M, Kwak HA, Wilson B, Bolotokova A, Wilson DJ, Harding RJ, Schapira M

ACS Omega. 2024-1-9 . 9(1):917-924 .doi: 10.1021/acsomega.3c07070

PMID: 38222562

2023

Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability.

Gall-Duncan T, Luo J, Jurkovic CM, Fischer LA, Fujita K, Deshmukh AL, Harding RJ, Tran S, Mehkary M, Li V, Leib DE, Chen R, Tanaka H, Mason AG, Lévesque D, Khan M, Razzaghi M, Prasolava T, Lanni S, Sato N, Caron MC, Panigrahi GB, Wang P, Lau R, Castel AL, Masson JY, Tippett L, Turner C, Spies M, La Spada AR, Campos EI, Curtis MA, Boisvert FM, Faull RLM, Davidson BL, Nakamori M, Okazawa H, Wold MS, Pearson CE

Cell. 2023-10-5 . .doi: 10.1016/j.cell.2023.09.008

PMID: 37827155