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

• Published in: bioRxiv
• Main Authors: Arrowsmith, Cheryl H, Ackloo, Suzanne, Li, Fengling, Szewczyk, Magda, Seitova, Almagul, Loppnau, Peter, Zeng, Hong, Ahmad, Shabbir, Beldar, Serap, Bolotokova, Albina, Chau, Irene, Dehghani-Tafti, Saba, Dong, Aiping, Ghiabi, Pegah, Gibson, Elisa, Green, Stuart R, Herasymenko, Oleksandra, Houliston, Scott, Hutchinson, Ashley, Kimani, Serah W, Kutera, Maria, Kwak, Haejin A, Li, Yanjun, Raquel Ac Machado, Perveen, Sumera, Righetto, Germanna L, Shrestha, Suman, Silva, Madhushika, Yadav, Manisha, Yazdi, Aliakbar K, Santhakumar, Vijayaratnam, Edwards, Aled M, Barsyte-Lovejoy, Dalia, Schapira, Matthieu, Brown, Peter J, Halabelian, Levon, Xu, Jin, Feng, Jianwen A, Kearnes, Steven, Thompson, James, Torng, Wen, Gilmer, Justin, Riley, Patrick, Watson, Ian, Arnautova, Yelena A, Baghaie, Aj, Cuozzo, John W, Disch, Jeremy S, Dumas, Antoine, Harms, Nathan, Liu, Jenny, Sigel, Eric A, Goldman, Brian, Kramer, Trevor, Mulhern, Christopher A, Slakman, Belinda L, Underkoffler, Carl, Moritz Von Rechenberg, Centrella, Paolo A, Clark, Matthew A, Marie-Aude Guie, Gullinger, John P, Keefe, Anthony D, Taylor, Rhys D, Zhang, Junyi, Zhang, Ying, Lento, Cristina, Wilson, Derek J, Wolf, Esther, Loup, Joachim, Sintchak, Michael D
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 04.03.2024
• Subjects: Drug discovery; Ligands; Protein families; Protein purification; Proteins
• DOI: 10.1101/2024.03.03.583197

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.Competing Interest StatementBLS, BG, JSD, JZ, JWC, MvR, PR, SK, and TK are employees and shareholders of Relay Therapeutics.Footnotes* https://zenodo.org/doi/10.5281/zenodo.10655440