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Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo
Christian Dubiella1, Benika J Pinch2,3,4, Kazuhiro Koikawa5,6,7
1Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
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.
Insights
Researchers developed Sulfopin, a novel covalent inhibitor targeting the Pin1 enzyme, which plays a role in cancer. This Pin1 inhibitor shows promise in reducing tumor progression and improving survival in preclinical cancer models.
Area of Science:
- Oncology
- Chemical Biology
- Drug Discovery
Background:
- Pin1 (peptidyl-prolyl isomerase) is implicated in cancer by activating oncogenes and inactivating tumor suppressors.
- Pin1 has been a challenging drug target despite its role in cancer progression.
Purpose of the Study:
- To identify and develop novel covalent inhibitors targeting Pin1's active site.
- To evaluate the efficacy of the developed inhibitor, Sulfopin, in preclinical cancer models.
Main Methods:
- Screening of an electrophilic fragment library to identify covalent inhibitors of Pin1.
- Validation of Sulfopin's selectivity using chemoproteomics.
- Assessment of cellular and in vivo target engagement and phenotypic effects.
- Testing Sulfopin in murine and zebrafish models of neuroblastoma and pancreatic cancer.
Main Results:
- Development of Sulfopin, a nanomolar covalent inhibitor of Pin1.
- Sulfopin demonstrated high selectivity and potent target engagement in vitro and in vivo.
- Pin1 inhibition by Sulfopin reduced c-Myc target gene expression, tumor progression, and improved survival in preclinical models.
- Sulfopin phenocopied genetic knockout of Pin1.
Conclusions:
- Sulfopin is a selective chemical probe for studying Pin1-dependent pharmacology.
- Pin1 inhibition offers a potential therapeutic strategy for MYCN-driven neuroblastoma and pancreatic cancer.
- Pin1 warrants further investigation as a viable cancer drug target.
