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PreprintCited by 24Computational Drug Discovery MethodsProtein Degradation and InhibitorsChemical Synthesis and Analysis

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A resource to enable chemical biology and drug discovery of WDR Proteins

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Ackloo, Suzanne, Li, Fengling, Szewczyk, Magda, Seitova, Almagul, Loppnau, Peter, Zeng, Hong, Xu, Jin, Ahmad, Shabbir, Arnautova, Yelena A, Baghaie, AJ, Beldar, Serap, Bolotokova, Albina, Centrella, Paolo A, Chau, Irene, Clark, Matthew A, Cuozzo, John W, Dehghani-Tafti, Saba, Disch, Jeremy S, Dong, Aiping, Dumas, Antoine, Feng, Jianwen A., Ghiabi, Pegah, Gibson, Elisa, Gilmer, Justin, Goldman, Brian, Green, Stuart R, Guié, Marie-Aude, Guilinger, John P, Harms, Nathan, Herasymenko, Oleksandra, Houliston, Scott, Hutchinson, Ashley, Kearnes, Steven, Keefe, Anthony D, Kimani, Serah W, Kramer, Trevor, Kutera, Maria, Kwak, Haejin A, Lento, Cristina, Li, Yanjun, Liu, Jenny, Loup, Joachim, Machado, Raquel AC, Mulhern, Christopher J, Perveen, Sumera, Righetto, Germanna L, Riley, Patrick, Shrestha, Suman, Sigel, Eric A, Silva, Madhushika, Sintchak, Michael D., Slakman, Belinda L, Taylor, Rhys D, Thompson, James, Torng, Wen, Underkoffler, Carl, von Rechenberg, Moritz, Watson, Ian, Wilson, Derek J, Wolf, Esther, Yadav, Manisha, Yazdi, Aliakbar K, Zhang, Junyi, Zhang, Ying, Santhakumar, Vijayaratnam, Edwards, Aled M, Barsyte-Lovejoy, Dalia, Schapira, Matthieu, Brown, Peter J, Halabelian, Levon, Arrowsmith, Cheryl H·2024·Journal of Medicinal Chemistry
DOI 10.1101/2024.03.03.583197PMC PMC11770632

Preprint — published as 10.1021/acs.jmedchem.4c02010

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Abstract

Protein class-focused drug discovery has a long and successful history in pharmaceutical research, yet most members of druggable protein families remain unliganded, often for practical reasons. Here we combined experiment and computation to enable discovery of ligands for WD40 repeat (WDR) proteins, one of the largest human protein families. This resource includes expression clones, purification protocols, and a comprehensive assessment of the druggability for hundreds of WDR proteins. We solved 21 high resolution crystal structures, and have made available a suite of biophysical, biochemical, and cellular assays to facilitate the discovery and characterization of small molecule ligands. To this end, we use the resource in a hit-finding pilot involving DNA-encoded library (DEL) selection followed by machine learning (ML). This led to the discovery of first-in-class, drug-like ligands for 9 of 20 targets. This result demonstrates the broad ligandability of WDRs. This extensive resource of reagents and knowledge will enable further discovery of chemical tools and potential therapeutics for this important class of proteins.

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Metadata

Authors
Ackloo, S., Li, F., Szewczyk, M., Seitova, A., Loppnau, P., Zeng, H., Xu, J., Ahmad, S., Arnautova, Y. A., Baghaie, A., Beldar, S., Bolotokova, A., Centrella, P. A., Chau, I., Clark, M. A., Cuozzo, J. W., Dehghani-Tafti, S., Disch, J. S., Dong, A., Dumas, A., Feng, J. A., Ghiabi, P., Gibson, E., Gilmer, J., Goldman, B., Green, S. R., Guié, M.-A., Guilinger, J. P., Harms, N., Herasymenko, O., Houliston, S., Hutchinson, A., Kearnes, S., Keefe, A. D., Kimani, S. W., Kramer, T., Kutera, M., Kwak, H. A., Lento, C., Li, Y., Liu, J., Loup, J., Machado, R. A., Mulhern, C. J., Perveen, S., Righetto, G. L., Riley, P., Shrestha, S., Sigel, E. A., Silva, M., Sintchak, M. D., Slakman, B. L., Taylor, R. D., Thompson, J., Torng, W., Underkoffler, C., von Rechenberg, M., Watson, I., Wilson, D. J., Wolf, E., Yadav, M., Yazdi, A. K., Zhang, J., Zhang, Y., Santhakumar, V., Edwards, A. M., Barsyte-Lovejoy, D., Schapira, M., Brown, P. J., Halabelian, L., & Arrowsmith, C. H.
Affiliations
  • University of Toronto (CA)
  • Google (United States) (US)
  • Relay Therapeutics (United States) (US)
  • York University (CA)
Corresponding author
  • Halabelian, Levon
  • Arrowsmith, Cheryl H
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
openRxiv
Published
2024-03-04
Volume
68
Issue
2
Pages
1092-1112
ISSN
0022-2623 (ISSN-L)
DOI
10.1101/2024.03.03.583197
PMC
PMC11770632
OpenAlex
W4404041923
Cited by
24
References
1
Citations by year
2026: 8 · 2025: 16
FWCI
5.08
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Medicinal Chemistry (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, S10OD021527, P30 GM124165, 06CH11357, DE-AC02-)
  • Boehringer Ingelheim
  • Bristol-Myers Squibb (875510)
  • Pfizer
  • Bayer (1097737, 875510)
  • McGill University
  • Genome Canada (875510, OGI- 196, 1097737)
  • Merck KGaA
  • Ontario Genomics (OGI-196)
  • European Federation of Pharmaceutical Industries and Associations (875510)
  • Ontario Genomics Institute (875510, OGI196)
  • University of Toronto
  • Innovative Medicines Initiative (875510)
  • National Institutes of Health (875510, 1097737, 1s10od021527-01, DE-AC02–06CH11357, OGI-196, GM124165)
  • Genentech (875510)
  • Office of Science (AC02‐06CH11357, DE-AC02, 06CH11357, DE-AC02-06CH11357)
  • Bristol-Myers Squibb Canada
  • Takeda Canada
  • National Institute of General Medical Sciences (DE-AC02-06CH11357, GM124165, P30GM124165)
  • Janssen Canada
  • Office of Research Infrastructure Programs, National Institutes of Health (S10OD021527)
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357, P30 GM124165)
  • Structural Genomics Consortium (1097737)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
Keywords
WD40 repeat proteins, ligandability, small-molecule ligands, DNA-encoded libraries, protein crystallography, protein biophysics, hit finding
MeSH terms
Machine Learning, WD40 Repeats, Humans, Ligands, Proteins, Small Molecule Libraries, Drug Discovery

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