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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:From a mechanism-based screening we have identified a novel Pin1 suicide inhibitor, KPT-6566, able to selectively inhibit Pin1 and target it for degradation. We have performed a transcriptiomic analysis comparing Pin1 specific RNA interference in MDA-MB 231 cells with KPT-6566 treatment to assess specificity of the KPT-6566 towards Pin1.

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

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

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Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells

Project description:Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but the mechanisms underlying their action and synergy remain elusive. ATRA inhibits APL, breast and liver cancers by targeting isomerase Pin1, a master regulator of oncogenic signaling. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, similar to Pin1 CRISPR knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic Pin1 inhibition by ATO and ATRA offers an attractive approach to combating breast and other cancers.

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Pin1/mutant-p53 jointly controlled genes

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Pin1/mutant-p53 jointly controlled genes

Project description:To investigate the specific gene expression program by which mutant-p53 and Pin1 control invasion and metastasis in breast cancer cells, we compared the transcriptomic profile of control, mutant-p53 depleted or Pin1 depleted MDA-MB-231 cells. MDA-MB-231 cells were transfected twice with siRNA against Pin1, p53 or LacZ as a control. Transfections were performed by using Lifofectamine 2000 (Invitrogen) according to manufacture's procedure. Forty-eight hours after second transfection, samples were then processed for total RNA extraction and hybridization on Affymetrix microarrays. Three biological replicas (A, B, C) were used for each of the three conditions, for a total of 9 samples

2011-05-30 | E-GEOD-26262 | biostudies-arrayexpress

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Project description:To discover the abnormal regulatory role of Pin1 in the ovarian cancer, The Pin1 full cDNA was knockIn (KI) the normal ovarian epithelium (Hose), and parallelly Pin1 was knockdown in the Ovarian cancer cells MCAS and sk-ov-3, and then compared the expression profiles of them to discovery the key features regulated by Pin1.

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Project description:The c-myc proto-oncogene is activated by translocation in Burkitt's lymphoma and substitutions in codon 58 stabilize the Myc protein or augment its oncogenic potential. In wild-type Myc, phosphorylation of Ser 62 and Thr 58 provide a landing pad for the peptidyl prolyl-isomerase Pin1, which in turn promotes Ser 62 dephosphorylation and Myc degradation. However, the role of Pin1 in Myc-induced lymphomagenesis remains unknown. We show here that genetic ablation of Pin1 reduces lymphomagenesis in EÂµ-myc transgenic mice. In both Pin1-deficient B-cells and MEFs, the proliferative response to Myc was selectively impaired, with no alterations in Myc-induced apoptosis or mitogen-induced cell cycle entry. This proliferative defect wasn't attributable to alterations in either Ser 62 phosphorylation or Myc-regulated transcription, but to the indirect activation of an Arf-p53 dependent cytostatic response. Pin1 silencing in lymphomas retarded disease progression in mice, making Pin1 an attractive therapeutic target in Myc-driven tumors. RNAseq samples of Pin1+/+ control (n=4), Pin1 -/- control (n=2), Pin1+/+ EÂµ-myc pre-tumoral (n=3), and Pin1-/- EÂµ-myc pre-tumoral (n=4) B cells.

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