ArticleNature chemical biology2026
High-throughput ligand diversification to discover chemical inducers of proximity.
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Article in Nature chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12citing papers in PubMed
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Who cites it
12 citing papers in PubMed.
- Broadening the molecular glue landscape.Nature chemical biology · 2026Article
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- Accelerate Your Science: Direct-to-Biology Strategies in Medicinal Chemistry.Journal of medicinal chemistry · 2026Review
- Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues.Science (New York, N.Y.) · 2026Article
- Generalized Analysis of Electrophilic Small Molecules.Angewandte Chemie (International ed. in English) · 2026Article
- Molecular glue degraders: Rational design, specificity engineering, and advanced delivery.Acta pharmaceutica Sinica. B · 2026Review
- A Global Ligandability Map of Tryptoline Butynamide Stereoprobes Identifies Covalent Inhibitors of the Actin Maturation Protease.Journal of the American Chemical Society · 2026Article
- Methods to Study the Molecular Mechanism and Drive the Design of Protein Degraders.Chemical reviews · 2026Review
- Localized heme sensing through a ternary molecular glue.bioRxiv : the preprint server for biology · 2026Article
- Proteome-Wide Discovery of Degradable Proteins Using Bifunctional Molecules.ACS central science · 2025Article
- Development of Chemical Tools for the Human YEATS Domain.ACS chemical biology · 2025Review
- SuFEx-enabled high-throughput medicinal chemistry for developing potent tamoxifen analogs as Ebola virus entry inhibitors.Frontiers in immunology · 2025Article
Corrections and comments
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Authors and funding
34 authors.
James B Shaum *Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID http://orcid.org/0000-0003-1664-1091
Miquel Muñoz I Ordoño *CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.ORCID http://orcid.org/0009-0003-4391-6393
Erica A SteenDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Daniela V WengeDivision of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-0064-9104
Hakyung CheongDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0009-0001-3330-3126
Jordan JanowskiDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID http://orcid.org/0000-0002-6990-5719
Moritz HunkelerDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0246-1188
Eric M BilottaDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID http://orcid.org/0000-0001-7609-3037
Zoe J RutterCentre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.
Paige A BartaDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Abby M ThornhillDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Natalia MilosevichDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Lauren M HargisDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Timothy R BishopDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Trever R CarterDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID http://orcid.org/0000-0001-5938-4043
Bryce da CamaraDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID http://orcid.org/0009-0002-2327-7240
Matthias HinterndorferCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.ORCID http://orcid.org/0000-0003-2435-4690
Lucas DadaDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.ORCID http://orcid.org/0000-0001-5846-0219
Wen-Ji HeDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Fabian OffenspergerCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
Hirotake FurihataCentre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.
Sydney R SchweberDivision of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0009-0004-2141-7224
Charlie HattonDivision of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-9903-4291
Yanhe WenDivision of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA.
Benjamin F CravattDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID http://orcid.org/0000-0001-5330-3492
Keary M EngleDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID http://orcid.org/0000-0003-2767-6556
Katherine A DonovanDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-8539-5106
Bruno MelilloDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.ORCID http://orcid.org/0000-0002-9708-5287
Seiya KitamuraDepartment of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
Alessio CiulliCentre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.ORCID http://orcid.org/0000-0002-8654-1670
Scott A ArmstrongDivision of Hematology/Oncology, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston Children's Hospital, and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-9099-4728
Eric S FischerDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0001-7337-6306
Georg E WinterCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gwinter@aithyra.at.ORCID http://orcid.org/0000-0001-6606-1437
Michael A ErbDepartment of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. michaelerb@scripps.edu.ORCID http://orcid.org/0000-0001-9993-3481
Funding
TYROSINE KINASE ONCOGENESIS IN MYELOID LEUKEMIAP01CA066996 · NCI · DANA-FARBER CANCER INSTITUTE · PI SCOTT A ARMSTRONG · 1996 to 2026
$52.5MChimeraX -- Next Generation Visualization and Analysis Software for Multiscale ModelingR01GM129325 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI FERRIN, THOMAS E · 2018 to 2025
$5.2MThe molecular basis of IMiD induced neo-substrate recruitment to the CRL4CRBN ubiquitin E3 ligase.R01CA214608 · NCI · DANA-FARBER CANCER INST · PI Eric Sebastian Fischer · 2017 to 2026
$4.0MTargeting crotonyl-lysine chromatin readers to disrupt pathogenic gene expression in leukemiaDP5OD026380 · OD · SCRIPPS RESEARCH INSTITUTE, THE · PI ERB, MICHAEL A · 2018 to 2022
$2.4MDefining epigenetic mechanisms in NPM1c mutant leukemiaR01CA259273 · NCI · DANA-FARBER CANCER INST · PI ARMSTRONG, SCOTT A · 2021 to 2025
$2.0MCancer-specific dependencies within the NuRD chromatin remodeler complex: new targets and chemical toolsR01CA280720 · NCI · SCRIPPS RESEARCH INSTITUTE, THE · PI Michael A Erb · 2024 to 2026
$1.7MExpanding the chemical probe development paradigm toward underexplored targetsR35GM155249 · NIGMS · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI Seiya Kitamura · 2024 to 2026
$1.3MCTSA Postdoctoral T32 at The Scripps Research InstituteT32TR004396 · NCATS · SCRIPPS RESEARCH INSTITUTE, THE · PI Katja A Lamia, Luc Teyton · 2024 to 2026
$770kA universal high-throughput platform to improve biological functions of small moleculesR00GM138758 · NIGMS · ALBERT EINSTEIN COLLEGE OF MEDICINE · PI KITAMURA, SEIYA · 2022 to 2023
$497kA universal high-throughput platform to improve biological functions of small moleculesK99GM138758 · NIGMS · SCRIPPS RESEARCH INSTITUTE, THE · PI KITAMURA, SEIYA · 2020 to 2021
$192kAustrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung) P7909, P36746, P5918723Deutsche Forschungsgemeinschaft (German Research Foundation) 511811315MEXT | Japan Society for the Promotion of Science (JSPS) 23KJ1669National Science Foundation (NSF) CHE-2046286NCATS NIH HHS T32 TR004396NCI NIH HHS P01 CA066996NCI NIH HHS R01 CA214608NCI NIH HHS R01 CA259273NCI NIH HHS R01 CA280720NIGMS NIH HHS K99 GM138758NIGMS NIH HHS R00 GM138758NIGMS NIH HHS R01 GM129325NIGMS NIH HHS R35 GM155249NIH HHS DP5 OD026380U.S. Department of Health & Human Services | National Institutes of Health (NIH) CA259273, CA066996U.S. Department of Health & Human Services | National Institutes of Health (NIH) K99GM138758, R35GM155249U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01CA214608U.S. Department of Health & Human Services | National Institutes of Health (NIH) T32TR004396U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA280720
Abstract
Chemical inducers of proximity (CIPs) stabilize biomolecular interactions, often causing an emergent rewiring of cellular biochemistry. While the discovery of heterobifunctional CIPs is expedited by rational design strategies, molecular glues have relied predominantly on serendipity. We hypothesized that preexisting ligands could be systematically decorated with chemical modifications to discover compounds that recruit proteins to a composite protein-ligand interface. Using sulfur(VI) fluoride exchange-based high-throughput chemistry (HTC) to install 3,163 structurally diverse building blocks onto ENL (eleven-nineteen leukemia) and BRD4 (bromodomain-containing protein 4) ligands, we screened each analog for degrader activity. This revealed dHTC1, an ENL degrader that recruits CRL4
Indexed as
High-Throughput Screening AssaysTranscription FactorsBromodomain Containing ProteinsCell Cycle ProteinsHumansLigandsNuclear ProteinsProtein BindingBRD4 protein, humanBromodomain Containing ProteinsCell Cycle ProteinsLigandsNuclear ProteinsTranscription Factors
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