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Discovery and Characterization of a Potent and Selective Pin1 Inhibitor Targeted to an Active Cysteine Site

ABSTRACT: Discovery and Characterization of a Potent and Selective Pin1 Inhibitor Targeted to an Active Cysteine Site

PROVIDER: PRJNA613908 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11364668.fastq.gz	Fastqsanger.gz
	SRR11364669.fastq.gz	Fastqsanger.gz
	SRR11364670.fastq.gz	Fastqsanger.gz
	SRR11364671.fastq.gz	Fastqsanger.gz
	SRR11364672.fastq.gz	Fastqsanger.gz

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Discovery and Characterization of a Potent and Selective Pin1 Inhibitor Targeted to an Active Cysteine Site

Project description:We report the development of rationally designed peptide inhibitors that covalently target Cys113, a highly conserved cysteine located in the Pin1 active site. The inhibitors were iteratively optimized for potency, selectivity, and cell permeability to give BJP-06-005-3, a versatile tool compound with which to probe Pin1 biology and interrogate its role in cancer, with the negative control compound BJP-06-115-3 (BJP-R). RNA-sequencing was performed to characterize the transcriptome-wide effects of 4h compound treatment.

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Project description: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. Still, 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 suitable chemical probe for assessing Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

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Expression data from Pin1 inhibitor ATRA and Pin1 knockdown

Project description:ATRA was identified as a Pin1 inhibitor via fluorescence polarization-based high throughput screening. We performed microarray expression profiling to demonstrate the similarity between ATRA and Pin1 KD at the genome-wide level APL NB4 cells in response to ATRRA or inducible Pin1 knockdown for 3 days were collected for RNA extraction and hybridization on Affymetrix microarrays. We sought to validate in genome-wide level whether similarity occurred between ATRA and Pin1 knockdown-treated NB4 cells.

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