A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins

  • J Med Chem. 2024 Nov 4. doi: 10.1021/acs.jmedchem.4c02010.
Suzanne Ackloo  1 ,  Fengling Li  1 ,  Magda Szewczyk  1 ,  Almagul Seitova  1 ,  Peter Loppnau  1 ,  Hong Zeng  1 ,  Jin Xu  2 ,  Shabbir Ahmad  1 ,  Yelena A Arnautova  3 ,  A J Baghaie  3 ,  Serap Beldar  1 ,  Albina Bolotokova  1 ,  Paolo A Centrella  4 ,  Irene Chau  1 ,  Matthew A Clark  4 ,  John W Cuozzo  3  5 ,  Saba Dehghani-Tafti  1 ,  Jeremy S Disch  3  5 ,  Aiping Dong  1 ,  Antoine Dumas  3 ,  Jianwen A Feng  2 ,  Pegah Ghiabi  1 ,  Elisa Gibson  1 ,  Justin Gilmer  2 ,  Brian Goldman  3  5 ,  Stuart R Green  1 ,  Marie-Aude Guié  4 ,  John P Guilinger  4 ,  Nathan Harms  3 ,  Oleksandra Herasymenko  1 ,  Scott Houliston  6 ,  Ashley Hutchinson  1 ,  Steven Kearnes  2  5 ,  Anthony D Keefe  4 ,  Serah W Kimani  1 ,  Trevor Kramer  3  5 ,  Maria Kutera  1 ,  Haejin A Kwak  1 ,  Cristina Lento  7 ,  Yanjun Li  1 ,  Jenny Liu  4 ,  Joachim Loup  8 ,  Raquel A C Machado  1 ,  Christopher J Mulhern  3  4 ,  Sumera Perveen  1 ,  Germanna L Righetto  1 ,  Patrick Riley  2  5 ,  Suman Shrestha  1 ,  Eric A Sigel  3 ,  Madhushika Silva  1 ,  Michael D Sintchak  9 ,  Belinda L Slakman  3  4  5 ,  Rhys D Taylor  4 ,  James Thompson  2 ,  Wen Torng  2 ,  Carl Underkoffler  3  5 ,  Moritz von Rechenberg  3  5 ,  Ryan T Walsh  4 ,  Ian Watson  2 ,  Derek J Wilson  7 ,  Esther Wolf  7 ,  Manisha Yadav  1 ,  Aliakbar K Yazdi  1 ,  Junyi Zhang  3  5 ,  Ying Zhang  4 ,  Vijayaratnam Santhakumar  1 ,  Aled M Edwards  1 ,  Dalia Barsyte-Lovejoy  1  10 ,  Matthieu Schapira  1  10 ,  Peter J Brown  1 ,  Levon Halabelian  1  10 ,  Cheryl H Arrowsmith  1  6
Affiliations
  • 1. Structural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
  • 2. Google, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.
  • 3. ZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
  • 4. X-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
  • 5. Relay Therapeutics, 399 Binney St., Cambridge, Massachusetts 02139, United States.
  • 6. Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada.
  • 7. Department of Chemistry, York University, Toronto, ON M3J 1P3, Canada.
  • 8. Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
  • 9. Civetta Therapeutics, 10 Wilson Rd., Cambridge, Massachusetts 02138, United States.
  • 10. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada.
PMID: 39495097 DOI: 10.1021/acs.jmedchem.4c02010
Abstract

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.

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