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Small molecule-mediated ERO1A inhibition in restraining aggressive breast cancer

ABSTRACT: Small molecule-mediated ERO1A inhibition in restraining aggressive breast cancer

PROVIDER: PRJEB77855 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR13382930.fastq.gz	Fastqsanger.gz
	ERR13382931.fastq.gz	Fastqsanger.gz
	ERR13382932.fastq.gz	Fastqsanger.gz
	ERR13382933.fastq.gz	Fastqsanger.gz
	ERR13382934.fastq.gz	Fastqsanger.gz

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Small molecule-mediated ERO1A inhibition in restraining aggressive breast cancer

Project description:Cancer cells adapt to harsh environmental conditions by inducing the Unfolded Protein Response (UPR), of which ERO1A is one of the mediators. ERO1A aids protein folding by acting as a protein disulfide oxidase, and under cancer-related hypoxia conditions, it favors the folding of angiogenic VEGFA, leading tumor cells to thrive and spread. The upregulation of ERO1A in cancer and the dispensability of ERO1A activity in healthy cells render ERO1 a perfect target for cancer therapy. Here, we report the upregulation of ERO1 in aggressive triple-negative breast cancer (TNBC) patients. Thus, we designed new ERO1A inhibitors in a campaign of lead compound optimization on the prototype EN460 to be tested in TNBC treatment. Cell-based screenings showed that I2 and I3, two novel EN460 analogs, inhibited ERO1A efficiently, thus blunting VEGFA secretion. Accordingly, in vitro assays to measure ERO1A engagement confirmed that I2 and I3 bind ERO1A. EN460, I2 and I3 triggered breast cancer cytotoxicity while specifically inhibiting ERO1A in a dose-dependent manner. I2 more efficiently impaired cancer-relevant features such as VEGFA secretion and the related cell migration. Furthermore, I2 impinged on the tumor microenvironment and viability of xenografts and syngeneic TNBC. Thus, ERO1A pharmacological inhibition promises to lead to an effective anti-cancer therapy for the yet incurable TNBC.

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Project description:Modification by ubiquitin controls the stability of most cellular proteins, and deregulation contributes to a variety of human diseases such as cancer. Deubiquitinases (DUBs) remove ubiquitin from proteins, and the inhibition of DUBs has been recognized as a therapeutic strategy to induce degradation of specific proteins, a concept extendable to ‘undruggable’ targets such as transcription factors. However, this potential has remained untapped; specific small molecule inhibitors for DUBs are scarce and insights into mechanisms of action are limited. Ubiquitin specific protease (USP) 7 stabilises the oncogenic E3 ligase MDM2 that destabilises the tumour suppressor p53 and inhibition of USP7 results in MDM2 degradation and p53 re-activation in a variety of cancers. We here present two small molecule inhibitors, FT671 and FT827, that inhibit USP7 with nanomolar affinity and display exquisite specificity towards USP7 in vitro and in cells. USP7-inhibitor co-crystal structures reveal that both compounds target the auto-inhibited apo-form of USP7 and bind in proximity to the misaligned catalytic triad in a dynamic hydrophobic pocket that serves as the binding site for the ubiquitin C-terminus. The unique auto-inhibited conformation of apo USP7 differs from other USP DUBs, explaining compound selectivity. Consistent with USP7 target engagement in cells, FT671 destabilises MDM2, stabilises p53 and results in transcription of p53 target genes, induction of the tumour suppressor p21, and tumour growth inhibition in vivo.

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