A Small Molecule Inhibitor of ETV1, YK-4-279, Prevents Prostate Cancer Growth and Metastasis in a Mouse Xenograft Model

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Abstract

Background

The erythroblastosis virus E26 transforming sequences ( ETS) family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. Chromosomal translocations fusing ETS factors to promoters of androgen responsive genes have been found in prostate cancers, including the most clinically aggressive forms. ERG and ETV1 are the most commonly translocated ETS proteins. Over-expression of these proteins in prostate cancer cells results in a more invasive phenotype. Inhibition of ETS activity by small molecule inhibitors may provide a novel method for the treatment of prostate cancer.

Methods and Findings

We recently demonstrated that the small molecule YK-4-279 inhibits biological activity of ETV1 in fusion-positive prostate cancer cells leading to decreased motility and invasion in-vitro. Here, we present data from an in-vivo mouse xenograft model. SCID-beige mice were subcutaneously implanted with fusion-positive LNCaP-luc-M6 and fusion-negative PC-3M-luc-C6 tumors. Animals were treated with YK-4-279, and its effects on primary tumor growth and lung metastasis were evaluated. YK-4-279 treatment resulted in decreased growth of the primary tumor only in LNCaP-luc-M6 cohort. When primary tumors were grown to comparable sizes, YK-4-279 inhibited tumor metastasis to the lungs. Expression of ETV1 target genes MMP7, FKBP10 and GLYATL2 were reduced in YK-4-279 treated animals. ETS fusion-negative PC-3M-luc-C6 xenografts were unresponsive to the compound. Furthermore, YK-4-279 is a chiral molecule that exists as a racemic mixture of R and S enantiomers. We established that (S)-YK-4-279 is the active enantiomer in prostate cancer cells.

Conclusion

Our results demonstrate that YK-4-279 is a potent inhibitor of ETV1 and inhibits both the primary tumor growth and metastasis of fusion positive prostate cancer xenografts. Therefore, YK-4-279 or similar compounds may be evaluated as a potential therapeutic tool for treatment of human prostate cancer at different stages.

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Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo

Gong-Hong Wei, Gwenael Badis, Michael F. Berger … (2010)

Members of the large ETS family of transcription factors (TFs) have highly similar DNA-binding domains (DBDs)—yet they have diverse functions and activities in physiology and oncogenesis. Some differences in DNA-binding preferences within this family have been described, but they have not been analysed systematically, and their contributions to targeting remain largely uncharacterized. We report here the DNA-binding profiles for all human and mouse ETS factors, which we generated using two different methods: a high-throughput microwell-based TF DNA-binding specificity assay, and protein-binding microarrays (PBMs). Both approaches reveal that the ETS-binding profiles cluster into four distinct classes, and that all ETS factors linked to cancer, ERG, ETV1, ETV4 and FLI1, fall into just one of these classes. We identify amino-acid residues that are critical for the differences in specificity between all the classes, and confirm the specificities in vivo using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for a member of each class. The results indicate that even relatively small differences in in vitro binding specificity of a TF contribute to site selectivity in vivo.

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Genomic and biochemical insights into the specificity of ETS transcription factors.

Peter Hollenhorst, Lawrence McIntosh, Barbara J. Graves (2011)

ETS proteins are a group of evolutionarily related, DNA-binding transcriptional factors. These proteins direct gene expression in diverse normal and disease states by binding to specific promoters and enhancers and facilitating assembly of other components of the transcriptional machinery. The highly conserved DNA-binding ETS domain defines the family and is responsible for specific recognition of a common sequence motif, 5'-GGA(A/T)-3'. Attaining specificity for biological regulation in such a family is thus a conundrum. We present the current knowledge of routes to functional diversity and DNA binding specificity, including divergent properties of the conserved ETS and PNT domains, the involvement of flanking structured and unstructured regions appended to these dynamic domains, posttranslational modifications, and protein partnerships with other DNA-binding proteins and coregulators. The review emphasizes recent advances from biochemical and biophysical approaches, as well as insights from genomic studies that detect ETS-factor occupancy in living cells.

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Small molecule selected to disrupt oncogenic protein EWS-FLI1 interaction with RNA Helicase A inhibits Ewing's Sarcoma

Hayriye Erkizan, Yali Kong, Melinda Merchant … (2009)

Many sarcomas and leukemias carry non-random chromosomal translocations encoding mutant fusion transcription factors that are essential to their molecular pathogenesis. These novel, tumor-specific proteins provides a unique opportunity for the development of highly selective anticancer drugs that has yet to be exploited. A particularly clear example is provided by Ewing's Sarcoma Family Tumors (ESFT) which contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precluded standard structure-based small molecule inhibitor design. Using surface plasmon resonance screening, we discovered a lead compound, NSC635437. A derivative compound, YK-4-279, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells, and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents.

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Author and article information

Contributors

Irina U. Agoulnik: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 5 December 2014

Volume: 9

Issue: 12

Electronic Location Identifier: e114260

Affiliations

[1 ]Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, United States of America

[2 ]The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States of America

Florida International University, United States of America

Author notes

* E-mail: au26@ 123456georgetown.edu

Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: USPTO awarded for YK-4-279 to Georgetown University, inventors include. Y.K., M.B., J.T. and A.Ü. A license agreement has been executed between Georgetown University and Tokalas Inc for these patents, in which J.T. is a founding share-holder. Georgetown University has filed patent applications on the YK-4279 as well as related compounds and derivatives of those molecules. Below is a summary of the issued and pending patent applications related to these compounds. I. “Targeting of EWS-FLI as Anti-Tumor Therapy” (GU Reference # 2006-041) 1. US Provisional application (60/877,856) filed December 29, 2006. 2. PCT/US07/089118 filed December 28, 2007. 3. US Provisional application (61/177,932) filed May 13, 2009. 4. US Non-provisional 12/494,191 filed June 29, 2009 ((CIP) claiming priority to both the PCT and US provisional applications; national phase entry of PCT); issued as US Patent 8,232,310. 5. US Non-provisional 12/720,616 filed March 9, 2010 (CONT). 6. Europe 07872364.0 filed December 28, 2007 (national phase entry of PCT). 7. Canada 2,711,003 filed December 28, 2007 (national phase entry of PCT). 8. Australia 2007341977 filed December 28, 2007 (national phase entry of PCT). 9. United States Provisional 61/405,170 filed October 20, 2010 (contains additional data). 10. Europe 13186704.6 divisional of Europe 07872364.0 priority to December 28, 2007. II. “Methods and Compositions for Treating Ewings Sarcoma Family of Tumors” (GU Reference #2012-019) 1. US Provisional Patent Application 61/623,349 filed April 12, 2012. 2. Patent Cooperation Treaty Application PCT/US2013/036234 filed April 11, 2013. III. “Methods and Compositions for Treating Cancer” (GU Reference #2014-012) 1. US Provisional Patent Application 61/895,308 filed October 24, 2013. All data in the manuscript are freely available. The authors acknowledge and follow all PLOS ONE policies on sharing data and materials. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: SR TM SHH SJ HC YSK JH ATK YK MAR MLB BK JAT AU. Performed the experiments: SR TM SHH SJ JH ATK MAR. Analyzed the data: SR SHH SJ ATK MAR BK AU. Contributed reagents/materials/analysis tools: SR HC YSK ATK YK MAR MLB BK JAT AU. Wrote the paper: SR AU.

Article

Publisher ID: PONE-D-14-22746

DOI: 10.1371/journal.pone.0114260

PMC ID: 4257561

PubMed ID: 25479232

SO-VID: de5f658e-8b48-4e35-ad60-8e4779e2a354

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 21 May 2014

Date accepted : 5 November 2014

Page count

Pages: 20

Funding

These experiments were primarily supported by a grant from the Department of Defense's Congressionally Directed Medical Research Program (PC111510, PI: Aykut Üren, http://cdmrp.army.mil/). The pharmacokinetic experiments were supported by the Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH grants P30 CA006973 and UL1 RR025005, and the Shared Instrument Grant (1S10RR026824-01), http://grants.nih.gov/grants/oer.htm). Biacore experiments were done at the Genomics and Epigenomics Shared Resource, which is supported by CCSG Grant P30 CA051008-16 (Lou Weiner, PI), http://cancercenters.cancer.gov/grants_funding/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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A Small Molecule Inhibitor of ETV1, YK-4-279, Prevents Prostate Cancer Growth and Metastasis in a Mouse Xenograft Model

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Abstract

Background

Methods and Findings

Conclusion

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PLOS Climate

Most cited references 25

Genome-wide analysis of ETS-family DNA-binding in vitro and in vivo

Genomic and biochemical insights into the specificity of ETS transcription factors.

Small molecule selected to disrupt oncogenic protein EWS-FLI1 interaction with RNA Helicase A inhibits Ewing's Sarcoma

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