ArticleNature chemical biology2021
Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.
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Article in Nature chemical biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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87citing papers in PubMed
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87 citing papers in PubMed, 142 citations in OpenAlex.
- Targeting MYC-Driven Cancers: From Oncogenic Addiction to Therapeutic Vulnerability.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- Interplay between NRF2 post-translational modifications and protein-protein interactions: Perspectives from emerging structural and functional evidence.Archives of biochemistry and biophysics · 2026Review
- Beyond KEAP1: The Context-Specific NRF2 Partner Code in Disease and Therapy.Antioxidants (Basel, Switzerland) · 2026Review
- Covalent Targeting of Histidine Residues: A Ligand-First Approach.Journal of medicinal chemistry · 2026Article
- Theaflavin-3,3'-Digallate Targets Pin1 to Suppress Hepatocellular Carcinoma Malignant Proliferation Through Modulation of MAPK and PI3K/AKT Signaling Pathways In Vitro.Biomolecules · 2026Article
- Systematic Optimization of Proteolysis-Targeting Chimeras for PIN1 Enables Selective Degradation and Antitumor Activity In Vivo.Pharmaceutics · 2026Article
- Developing virtual physiology of human tumor tissue for malignancy assessment.NPJ precision oncology · 2026Article
- Discovery of a First-in-Class Covalent Allosteric SHP1 Inhibitor with Immunotherapeutic Activity.Angewandte Chemie (International ed. in English) · 2026Article
- Developments and challenges in hit progression within fragment-based drug discovery.Nature communications · 2026Review
- Scaffold Hopping and Optimization of Thiazole Hybrids as Selective PIN1 Inhibitors: A Computational Study.Medicinal chemistry (Shariqah (United Arab Emirates)) · 2026Article
- Pre-clinical evaluation of a potent and effective Pin1-degrading agent in pancreatic cancer.Molecular therapy. Oncology · 2025Article
- The Prolyl Isomerase PIN1 Affects Fibroblast Differentiation States and Cross-talk in Pancreatic Cancer.Cancer research · 2025Article
- Ginsenoside Rh2 as a novel PIN1 inhibitor disrupting the cancer stem cell-like phenotype in non-small cell lung cancer.Journal of translational medicine · 2025Article
- A polymeric nanovesicle delivers sulfopin and gemcitabine to remodel tumor microenvironment for enhanced chemoimmunotherapy against orthotopic pancreatic cancer.Materials today. Bio · 2025Article
- Programmable immunoprobiotics orchestrate antitumor immune response with Pin1 inhibition for pancreatic cancer treatment.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Gas Phase Separation of Modified Peptides for Activity-Based Protein Profiling.Analytical chemistry · 2025Article
- Covalent Inhibition of the Peptidyl-Prolyl Isomerase Pin1 by Sulfopin Results in a Broad Impact on the Phosphoproteome of Human Osteosarcoma U2-OS Cells.Proteomics · 2025Article
- Targeting MYC: Multidimensional regulation and therapeutic strategies in oncology.Genes & diseases · 2025Review
- TGF-β inhibition restores hematopoiesis and immune balance via bone marrow EPCs in aplastic anemia.Experimental & molecular medicine · 2025Article
- Delineating cysteine-reactive compound modulation of cellular proteostasis processes.Nature chemical biology · 2025Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
44 authors at 10 institutions in 7 countries.
Christian Dubiella *Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0000-0001-5801-2053
Benika J Pinch *Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-2957-6903
Kazuhiro KoikawaDepartment of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Daniel ZaidmanDepartment of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Evon PoonDivision of Clinical Studies, The Institute of Cancer Research, London, UK.
Theresa D ManzDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Behnam NabetDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-6738-4200
Shuning HeDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Efrat ResnickDepartment of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Adi RogelDepartment of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
Ellen M LangerDepartment of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.ORCID http://orcid.org/0000-0003-0352-1859
Colin J DanielDepartment of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
Hyuk-Soo SeoDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0646-2102
Ying ChenCollege of Chemistry and Molecular Engineering, Peking University, Beijing, China.
Guillaume AdelmantDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Shabnam SharifzadehDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Scott B FicarroDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Yann JaminDivision of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.
Barbara Martins da CostaDivision of Clinical Studies, The Institute of Cancer Research, London, UK.
Mark W ZimmermanDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-2489-3889
Xiaolan LianDepartment of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Shin KibeDepartment of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8197-0313
Shingo KozonoDepartment of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3898-6373
Zainab M DoctorDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Christopher M BrowneDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Annan YangDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-6750-0304
Liat Stoler-BarakDepartment of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Richa B ShahDepartment of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nicholas E VangosDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Ezekiel A GeffkenDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Roni OrenDepartment of Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel.
Eriko KoideDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0002-8289-1542
Samuel SidiDepartment of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ziv ShulmanDepartment of Immunology, The Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0000-0002-9604-212X
Chu WangCollege of Chemistry and Molecular Engineering, Peking University, Beijing, China.ORCID http://orcid.org/0000-0002-6925-1268
Jarrod A MartoDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-2086-1134
Sirano Dhe-PaganonDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0824-5929
Thomas LookDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Xiao Zhen ZhouDepartment of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Kun Ping LuDepartment of Medicine, Division of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Rosalie C SearsDepartment of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.ORCID http://orcid.org/0000-0003-1558-2413
Louis CheslerDivision of Clinical Studies, The Institute of Cancer Research, London, UK.
Nathanael S GrayDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA. nsgray01@stanford.edu.ORCID http://orcid.org/0000-0001-5354-7403
Nir LondonDepartment of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel. nir.london@weizmann.ac.il.ORCID http://orcid.org/0000-0003-2687-0699
Harvard University · USWeizmann Institute of Science · ILBroad Institute · USDana-Farber Cancer Institute · USBrigham and Women's Hospital · USInstitute of Cancer Research · GBOregon Health & Science University · USPeking University · CNThe Graduate Center, CUNY · USBoston Children's Hospital · US
Funding
Overall EvaluationP41GM103403 · NIGMS · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2012 to 2017
$14.3MTraining in Pharmacological SciencesT32GM007306 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI GOLAN, DAVID E. · 1985 to 2018
$6.6MHydroxylation regulation of c-MycR01CA186241 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI Mu-Shui Dai, ROSALIE C SEARS · 2015 to 2026
$4.2MPrinciples of Scientific Citizenship: Ethics, Communication, and Leadership for ScientistsT32GM095450 · NIGMS · HARVARD UNIVERSITY · PI WALKER, SUZANNE · 2011 to 2020
$3.5MDevelopment of selective Pin1 inhibitors to target a common oncogenic mechanismR01CA205153 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI GRAY, NATHANAEL SCHIANDER, WULF, GERBURG M · 2017 to 2021
$3.3MNovel Screening Platform for Discovery of DUB Targeting ProbesR01CA233800 · NCI · DANA-FARBER CANCER INST · PI BUHRLAGE, SARA J, MARTO, JARROD A. · 2019 to 2022
$2.5MA Non-Canonical IRAK1 Signaling Pathway Triggered by Ionizing RadiationR01GM135301 · NIGMS · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Samuel Sidi · 2019 to 2026
$2.4MThe Role of post-translational activation of Myc in pancreatic cancerR01CA196228 · NCI · OREGON HEALTH & SCIENCE UNIVERSITY · PI SEARS, ROSALIE C · 2015 to 2019
$2.0MDevelopment of covalent Pin1 inhibitors for the treatment of triple negative breast cancerF31CA225066 · NCI · HARVARD UNIVERSITY · PI PINCH, BENIKA JOAN · 2018 to 2019
$62kCancer Research UK 28278Cancer Research UK C34648/A14610Cancer Research UK C34648/A18339NCI NIH HHS F31 CA225066NCI NIH HHS R01 CA186241NCI NIH HHS R01 CA196228NCI NIH HHS R01 CA205153NCI NIH HHS R01 CA233800NIGMS NIH HHS P41 GM103403NIGMS NIH HHS R01 GM135301NIGMS NIH HHS T32 GM007306NIGMS NIH HHS T32 GM095450
Abstract
The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.
Indexed as
AnimalsAntineoplastic AgentsApoptosisCell ProliferationCell SurvivalDose-Response Relationship, DrugDrug Screening Assays, AntitumorEnzyme InhibitorsHumansMiceMice, Inbred C57BLMolecular StructureNeoplasms, ExperimentalNIMA-Interacting Peptidylprolyl IsomeraseProto-Oncogene Proteins c-mycStructure-Activity RelationshipAntineoplastic AgentsEnzyme InhibitorsMYC protein, humanNIMA-Interacting Peptidylprolyl IsomerasePIN1 protein, humanProto-Oncogene Proteins c-myc
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