Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo
| Autor: | Sirano Dhe-Paganon, Benika J. Pinch, Mark W. Zimmerman, Richa B. Shah, Kun Ping Lu, Jarrod A. Marto, Shuning He, Eriko Koide, Daniel Zaidman, Christopher M. Browne, Ziv Shulman, Barbara Martins da Costa, Christian Dubiella, Evon Poon, Guillaume Adelmant, Nir London, Xiao Zhen Zhou, Chu Wang, Ellen M. Langer, Kazuhiro Koikawa, Theresa D. Manz, Thomas Look, Xiaolan Lian, Hyuk-Soo Seo, Annan Yang, Louis Chesler, Ezekiel A. Geffken, Liat Stoler-Barak, Shin Kibe, Efrat Resnick, Nicholas E. Vangos, Shabnam Sharifzadeh, Shingo Kozono, Colin J. Daniel, Scott B. Ficarro, Roni Oren, Ying Chen, Nathanael S. Gray, Rosalie C. Sears, Samuel Sidi, Adi Rogel, Zainab M. Doctor, Behnam Nabet, Yann Jamin |
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| Rok vydání: | 2020 |
| Předmět: |
Cell Survival
Antineoplastic Agents Apoptosis Article Proto-Oncogene Proteins c-myc 03 medical and health sciences Mice Structure-Activity Relationship Downregulation and upregulation In vivo Pancreatic cancer Neuroblastoma medicine Tumor Cells Cultured Animals Humans Chemoproteomics Enzyme Inhibitors Molecular Biology 030304 developmental biology Cell Proliferation 0303 health sciences Dose-Response Relationship Drug Molecular Structure Chemistry 030302 biochemistry & molecular biology Cancer Cell Biology Neoplasms Experimental medicine.disease Mice Inbred C57BL NIMA-Interacting Peptidylprolyl Isomerase Tumor progression Cancer research PIN1 Drug Screening Assays Antitumor |
| Zdroj: | Nat Chem Biol |
| ISSN: | 1552-4469 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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