A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins
Target class-focused drug discovery has a strong track record in pharmaceutical research, yet public domain data indicate that many members of protein families remain unliganded. Here we present a systematic approach to scale up the discovery and characterization of small molecule ligands for the WD40 repeat (WDR) protein family. We developed a comprehensive suite of protocols for protein production, crystallography, and biophysical, biochemical, and cellular assays. A pilot hit-finding campaign using DNA-encoded chemical library selection followed by machine learning (DEL-ML) to predict ligands from virtual libraries yielded first-in-class, drug-like ligands for 7 of the 16 WDR domains screened, thus demonstrating the broader ligandability of WDRs. This study establishes a template for evaluation of protein family wide ligandability and provides an extensive resource of WDR protein biochemical and chemical tools, knowledge, and protocols to discover potential therapeutics for this highly disease-relevant, but underexplored target class.
Authors
- James Thompson (ORCID: https://orcid.org/0000-0002-9285-1317)
- Patrick Riley (ORCID: https://orcid.org/0000-0003-0797-0272)
- Anthony D. Keefe (ORCID: https://orcid.org/0000-0003-4548-2835)
- Magda Szewczyk
- Yelena A. Arnautova (ORCID: https://orcid.org/0000-0001-9282-6739)
- Matthew A. Clark
- Moritz von Rechenberg
- Brian Goldman
- John P. Guilinger
- Jeremy S. Disch (ORCID: https://orcid.org/0000-0002-0357-1672)
- Serah Kimani (ORCID: https://orcid.org/0000-0002-6960-3833)
- Junyi Zhang (ORCID: https://orcid.org/0000-0002-2392-1967)
- P. Loppnau (ORCID: https://orcid.org/0009-0004-0002-355X)
- C.H. Arrowsmith (ORCID: https://orcid.org/0000-0002-4971-3250)
- Sumera Perveen (ORCID: https://orcid.org/0000-0002-8898-9540)
- Raquel A. C. Machado (ORCID: https://orcid.org/0000-0001-5912-2991)
- Jianwen A. Feng (ORCID: https://orcid.org/0009-0002-6077-1635)
- A.M. Edwards (ORCID: https://orcid.org/0000-0002-4782-6016)
- Levon Halabelian (ORCID: https://orcid.org/0000-0003-4361-3619)
- Albina Bolotokova
- Irene Chau (ORCID: https://orcid.org/0000-0002-2313-973X)
- Justin Gilmer (ORCID: https://orcid.org/0000-0002-6915-5591)
- Cristina Lento (ORCID: https://orcid.org/0000-0002-4205-1725)
- Belinda L. Slakman (ORCID: https://orcid.org/0000-0002-9621-9589)
- Ian Robert Watson (ORCID: https://orcid.org/0000-0002-6025-3080)
- Steven Kearnes (ORCID: https://orcid.org/0000-0003-4579-4388)
- Eric A. Sigel
- Rhys Dylan Taylor
- Derek J. Wilson (ORCID: https://orcid.org/0000-0002-7012-6085)
- Michael D. Sintchak (ORCID: https://orcid.org/0000-0003-2947-6566)
- Elisa Gibson (ORCID: https://orcid.org/0000-0002-7112-337X)
- Haejin Angela Kwak (ORCID: https://orcid.org/0000-0002-5537-681X)
- Esther Wolf (ORCID: https://orcid.org/0009-0005-9676-3807)
- Maria Kutera
- Serap Beldar (ORCID: https://orcid.org/0000-0002-7601-4543)
- Christopher J. Mulhern
- Germanna Lima Righetto (ORCID: https://orcid.org/0000-0002-6915-1187)
- Almagul Seitova
- Scott Houliston (ORCID: https://orcid.org/0000-0002-0113-0339)
- Vijayaratnam Santhakumar (ORCID: https://orcid.org/0000-0002-7001-557X)
- Trevor J. Kramer
- Jin Xu (ORCID: https://orcid.org/0000-0003-2289-4896)
- John W. Cuozzo (ORCID: https://orcid.org/0000-0002-6229-0395)
- Stuart R. Green (ORCID: https://orcid.org/0000-0002-2960-9683)
- Wen Torng (ORCID: https://orcid.org/0000-0002-8877-4785)
- Carl Underkoffler (ORCID: https://orcid.org/0000-0002-7939-0018)
- Matthieu Schapira (ORCID: https://orcid.org/0000-0002-1047-3309)
- Dalia Barsyte-Lovejoy
- Pegah Ghiabi
- Shabbir Ahmad (ORCID: https://orcid.org/0000-0003-2374-1197)
- Paolo A. Centrella
- Marie-Aude Guié
- Nathan Harms (ORCID: https://orcid.org/0000-0003-2680-371X)
- Peter J. Brown (ORCID: https://orcid.org/0000-0002-8454-0367)
- Hong Zeng
- Ryan T. Walsh (ORCID: https://orcid.org/0000-0003-3308-5496)
- Suzanne Ackloo (ORCID: https://orcid.org/0000-0002-9696-1839)
- Arrash J. Baghaie
- Joachim Loup
- Antoine Dumas
- Saba Dehghani-Tafti
- Yanjun Li (ORCID: https://orcid.org/0000-0002-9512-5265)
- Ying Zhang (ORCID: https://orcid.org/0000-0002-6910-273X)
- Manisha Yadav (ORCID: https://orcid.org/0000-0001-6559-7774)
- Suman Shrestha (ORCID: https://orcid.org/0000-0002-7011-7496)
- Fengling Li (ORCID: https://orcid.org/0000-0001-9530-2068)
- Jenny Liu
- Ashley Hutchinson (ORCID: https://orcid.org/0000-0002-3481-8025)
- Madhushika Silva (ORCID: https://orcid.org/0009-0001-7060-0445)
- Oleksandra Herasymenko (ORCID: https://orcid.org/0000-0002-1176-1476)
- Aliakbar Khalili Yazdi
- Aiping Dong
Institutions
- Google (United States) (US)
- University of Toronto (CA)
- York University (CA)
- Princess Margaret Cancer Centre (CA)
- Structural Genomics Consortium (CA)
- Relay Therapeutics (United States) (US)
- Cara Therapeutics (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-04
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02010
- Citations
- 18
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- U.S. Department of Energy
- Boehringer Ingelheim
- Bristol-Myers Squibb
- Pfizer
- Bayer
- McGill University
- Genome Canada
- Merck KGaA
- Ontario Genomics
- European Federation of Pharmaceutical Industries and Associations
- Ontario Genomics Institute
- University of Toronto
- Innovative Medicines Initiative
- National Institutes of Health
- Genentech
- Office of Science
- Bristol-Myers Squibb Canada
- Takeda Canada
- National Institute of General Medical Sciences
- Janssen Canada
- Office of Research Infrastructure Programs, National Institutes of Health
- Argonne National Laboratory