Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo

• Published in: Nature chemical biology Vol. 17; no. 9; pp. 954 - 963
• Main Authors: Dubiella, Christian, Pinch, Benika J., Koikawa, Kazuhiro, Zaidman, Daniel, Poon, Evon, Manz, Theresa D., Nabet, Behnam, He, Shuning, Resnick, Efrat, Rogel, Adi, Langer, Ellen M., Daniel, Colin J., Seo, Hyuk-Soo, Chen, Ying, Adelmant, Guillaume, Sharifzadeh, Shabnam, Ficarro, Scott B., Jamin, Yann, Martins da Costa, Barbara, Zimmerman, Mark W., Lian, Xiaolan, Kibe, Shin, Kozono, Shingo, Doctor, Zainab M., Browne, Christopher M., Yang, Annan, Stoler-Barak, Liat, Shah, Richa B., Vangos, Nicholas E., Geffken, Ezekiel A., Oren, Roni, Koide, Eriko, Sidi, Samuel, Shulman, Ziv, Wang, Chu, Marto, Jarrod A., Dhe-Paganon, Sirano, Look, Thomas, Zhou, Xiao Zhen, Lu, Kun Ping, Sears, Rosalie C., Chesler, Louis, Gray, Nathanael S., London, Nir
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2021; Nature Publishing Group
• Subjects: 631/92/2132; 631/92/556; 631/92/613; 631/92/96; Animal models; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; c-Myc protein; Cancer; Cell Biology; Cell Proliferation - drug effects; Cell Survival - drug effects; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Covalence; Danio rerio; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; In vivo methods and tests; Mice; Mice, Inbred C57BL; Molecular Structure; Myc protein; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Neuroblastoma; NIMA-Interacting Peptidylprolyl Isomerase - antagonists & inhibitors; NIMA-Interacting Peptidylprolyl Isomerase - metabolism; Pancreatic cancer; Peptidylprolyl isomerase; Pharmacology; Pin1 protein; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - metabolism; Structure-Activity Relationship; Suppressors; Therapeutic targets; Tumor Cells, Cultured; Tumors; Zebrafish
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-021-00786-7

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. The development of Sulfopin, a highly selective and potent, covalent Pin1 inhibitor that phenocopies Pin1 knockout and regresses tumors in murine and zebrafish models of neuroblastoma as well as in a pancreatic cancer mouse model.