ArticleJournal of medicinal chemistry2025
A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.
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Article in Journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16citing papers in PubMed
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Who cites it
16 citing papers in PubMed.
- Affinity selection mass spectrometry screening discovers new COP1 peptide binders.RSC chemical biology · 2026Article
- WDR12 Promotes Glucose Metabolism via PFKFB4 Upregulation in Gastric Cancer.Cancer science · 2026Article
- Site-Specific Hydrogen-Deuterium Exchange Mass Spectrometry for Deep Explorations of Dynamic Shifts in Protein-Drug Interactions.Journal of the American Chemical Society · 2026Article
- The role of the WD40-repeat protein family in cancer.Molecular cancer · 2026Review
- RACK1 in host immune response to infections: molecular mechanisms and therapeutic potentials.Frontiers in immunology · 2026Review
- Enantioselective protein affinity selection mass spectrometry (E-ASMS).Nature communications · 2025Article
- Enabling Open Machine Learning of Deoxyribonucleic Acid-Encoded Library Selections to Accelerate the Discovery of Small Molecule Protein Binders.Journal of medicinal chemistry · 2025Article
- Tryptoline Stereoprobe Elaboration Identifies Inhibitors of the GRPEL1-HSPA9 Chaperone Complex.bioRxiv : the preprint server for biology · 2025Article
- Discovering Uncharted Binding Pockets on E3 Ligases Leads to the Identification of FBW7 Allosteric Modulators.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Site-Specific Hydrogen Deuterium Exchange Difference Mass Spectrometry Measurements for Ligand Binding.Journal of the American Society for Mass Spectrometry · 2025Article
- Extending quantum-mechanical benchmark accuracy to biological ligand-pocket interactions.Nature communications · 2025Article
- Protein-ligand data at scale to support machine learning.Nature reviews. Chemistry · 2025Review
- OICR-41103 as a chemical probe for the DCAF1 WD40 domain.Communications biology · 2025Article
- Disease-causing mutations in the G protein β5 β-propeller disrupt its chaperonin-mediated folding trajectory.bioRxiv : the preprint server for biology · 2025Article
- A Selective MAP3K1 Inhibitor Facilitates Discovery of NPM1 as a Member of the Network.Molecules (Basel, Switzerland) · 2025Article
- Potent and selective SETDB1 covalent negative allosteric modulator reduces methyltransferase activity in cells.Nature communications · 2025Article
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Authors and funding
72 authors.
Suzanne AcklooStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0002-9696-1839
Fengling LiStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Magda SzewczykStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Almagul SeitovaStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Peter LoppnauStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Hong ZengStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Jin XuGoogle, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.
Shabbir AhmadStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Yelena A ArnautovaZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
A J BaghaieZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Serap BeldarStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Albina BolotokovaStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Paolo A CentrellaX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Irene ChauStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Matthew A ClarkX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.ORCID 0009-0002-9577-8685
John W CuozzoZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.ORCID 0000-0002-6229-0395
Saba Dehghani-TaftiStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Jeremy S DischZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.ORCID 0000-0002-0357-1672
Aiping DongStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Antoine DumasZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Jianwen A FengGoogle, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.ORCID 0000-0003-1221-7605
Pegah GhiabiStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Elisa GibsonStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0002-7112-337X
Justin GilmerGoogle, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.
Brian GoldmanZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Stuart R GreenStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0002-2960-9683
Marie-Aude GuiéX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
John P GuilingerX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Nathan HarmsZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Oleksandra HerasymenkoStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Scott HoulistonPrincess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada.
Ashley HutchinsonStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Steven KearnesGoogle, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.ORCID 0000-0003-4579-4388
Anthony D KeefeX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Serah W KimaniStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0002-6960-3833
Trevor KramerZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Maria KuteraStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Haejin A KwakStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Cristina LentoDepartment of Chemistry, York University, Toronto, ON M3J 1P3, Canada.
Yanjun LiStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Jenny LiuX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Joachim LoupDepartment of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
Raquel A C MachadoStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0001-5912-2991
Christopher J MulhernZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Sumera PerveenStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Germanna L RighettoStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Patrick RileyGoogle, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.ORCID 0000-0003-0797-0272
Suman ShresthaStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Eric A SigelZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Madhushika SilvaStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Michael D SintchakCivetta Therapeutics, 10 Wilson Rd., Cambridge, Massachusetts 02138, United States.ORCID 0000-0003-2947-6566
Belinda L SlakmanZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.ORCID 0000-0002-9621-9589
Rhys D TaylorX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
James ThompsonGoogle, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.
Wen TorngGoogle, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.ORCID 0000-0002-8877-4785
Carl UnderkofflerZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Moritz von RechenbergZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Ryan T WalshX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.ORCID 0000-0003-3308-5496
Ian WatsonGoogle, 1600 Amphitheatre Parkway, Mountain View, California 94043, United States.
Derek J WilsonDepartment of Chemistry, York University, Toronto, ON M3J 1P3, Canada.ORCID 0000-0002-7012-6085
Esther WolfDepartment of Chemistry, York University, Toronto, ON M3J 1P3, Canada.
Manisha YadavStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0001-6559-7774
Aliakbar K YazdiStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Junyi ZhangZebiAI Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Ying ZhangX-Chem Inc., 100 Beaver St., Waltham, Massachusetts 02435, United States.
Vijayaratnam SanthakumarStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0002-7001-557X
Aled M EdwardsStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0002-4782-6016
Dalia Barsyte-LovejoyStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Matthieu SchapiraStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0002-1047-3309
Peter J BrownStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Levon HalabelianStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.ORCID 0000-0003-4361-3619
Cheryl H ArrowsmithStructural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.
Funding
User Training and OutreachP30GM124165 · NIGMS · CORNELL UNIVERSITY · PI STEVEN E EALICK · 2018 to 2026
$34.2MPixel Array Detector for Macromolecular CrystallographyS10OD021527 · OD · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2016 to 2016
$2.0MNIGMS NIH HHS P30 GM124165NIH HHS S10 OD021527
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.
Indexed as
WD40 RepeatsDrug DiscoveryHumansLigandsMachine LearningProteinsSmall Molecule LibrariesLigandsProteinsSmall Molecule Libraries
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.