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BioAssay: AID 651667

Broad Institute Identification of small molecule inhibitor of the ETS Transcription Factor Rearrangement EWS/FLI transcriptional activity in Ewing's Sarcoma Probe Project

Transcription factors coordinate the expression of sets of genes that are critical for normal development and physiology. Perturbations in transcription factor function underlie the pathophysiology of a number of diseases, including chromosomal translocations that result in chimeric transcription factors that are associated with the development of several types of cancers. Ewing sarcoma is a more ..
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AID: 651667
Data Source: Broad Institute (7014_Inhibitor_Project)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2012-10-19
Modify Date: 2012-11-06
Related Experiments
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AIDNameTypeComment
651661Luminescence Cell-Based Primary HTS to identify inhibitors of the oncoprotein EWS/Fli transcriptional activity Measured in Cell-Based System Using Plate Reader - 7014-01_Inhibitor_SinglePoint_HTS_ActivityScreeningdepositor-specified cross reference: Primary screen
686920Luminescence Cell-Based Primary HTS to identify inhibitors of the oncoprotein EWS/Fli transcriptional activity Measured in Cell-Based System Using Plate Reader - 7014-01_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
720570Luminescence cell-based Retest at Dose assay to determine EWS/Fli1 dependent TC71 mammalian cell cytotoxity Measured in Cell-Based System Using Plate Reader - 7014-04_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
720586Fluorescence polarization acridine orange assay to identify DNA binding small molcules Measured in Biochemical System Using Plate Reader - 7014-02_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
720587Luminescence cell-based Retest at Dose assay to determine EWS/Fli1 dependent A673 mammalian cell cytotoxity Measured in Cell-Based System Using Plate Reader - 7014-03_Inhibitor_Dose_CherryPick_ActivityConfirmatorydepositor-specified cross reference
720588HEK293 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-01_Inhibitor_Dose_CherryPick_Activity_Set3Confirmatorydepositor-specified cross reference
720589HepG2 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-02_Inhibitor_Dose_CherryPick_Activity_Set3Confirmatorydepositor-specified cross reference
743470HEK293 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader_7071-01_Inhibitor_Dose_DryPowder_Activity_Set15Confirmatorydepositor-specified cross reference
743471HepG2 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-02_Inhibitor_Dose_DryPowder_Activity_Set12Confirmatorydepositor-specified cross reference
743472A549 Cytotoxicity Assay Measured in Cell-Based System Using Plate Reader - 7071-06_Inhibitor_Dose_DryPowder_Activity_Set12Confirmatorydepositor-specified cross reference
743477Luminescence cell-based Retest at Dose assay to determine EWS/Fli1 dependent TC71 mammalian cell cytotoxity Measured in Cell-Based System Using Plate Reader - 7014-04_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
743478Luminescence cell-based Retest at Dose assay to determine EWS/Fli1 dependent A673 mammalian cell cytotoxity Measured in Cell-Based System Using Plate Reader - 7014-03_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
743479Luminescence Cell-Based Primary HTS to identify inhibitors of the oncoprotein EWS/Fli transcriptional activity Measured in Cell-Based System Using Plate Reader - 7014-01_Inhibitor_Dose_DryPowder_ActivityConfirmatorydepositor-specified cross reference
Description:
Primary Collaborators:
Andrew Kung,Dana-Farber Cancer Institute,Boston, MA,andrew_kung@dfci.harvard.edu
Kimberly Stegmaier,Dana-Farber Cancer Institute,Boston, MA,kimberly_stegmaier@dcfi.harvard.edu
Changmin Chen,Dana-Farber Cancer Institute,Boston, MA,Changmin_Chen@dfci.harvard.edu
Brian Crompton,Children's Hospital,Boston, MA,Brian.Crompton@childrens.harvard.edu

Project Goal:

Transcription factors coordinate the expression of sets of genes that are critical for normal development and physiology. Perturbations in transcription factor function underlie the pathophysiology of a number of diseases, including chromosomal translocations that result in chimeric transcription factors that are associated with the development of several types of cancers. Ewing sarcoma is a pediatric and young adult cancer that results from a translocation that fuses the DNA binding domain of the Friend leukemia virus integration 1 (FLI1) transcription factor to the transactivation domain of the EWS protein, forming the EWS/FLI oncoprotein. Ewing sarcoma cells have a strict dependency on the EWS/FLI oncoprotein, and experimental modulation of EWS/FLI activity (e.g., RNAi knock-down, antisense RNA) results in tumor cell apoptosis, cell cycle arrest, and loss of tumorigenicity. The central role of EWS/FLI in Ewing sarcoma tumorigenesis makes it a propitious target for drug development; however transcription factor oncoproteins have largely been refractory to conventional drug discovery approaches and are generally considered "undruggable."

Many pediatric cancers, in principle, are ideally suited for the development of targeted transcription factor therapies because several of these diseases are causally linked to single genetically encoded oncogenes. Ewing sarcoma cells, for example, have a strict dependency on the EWS/FLI oncoprotein and are thus "oncogene-addicted" to ongoing EWS/FLI activity. While the EWS/FLI transcription factor rearrangement was discovered over 15 years ago, successful therapy targeting this transcription factor abnormality has yet to be developed, and new therapies for this disease are very much needed. The vast majority of children with metastastic Ewing sarcoma will relapse after multimodality therapy, and relapse is almost uniformly fatal. Moreover, even for children who are cured, long-term morbidity of cytotoxic treatment is significant. There remains an urgent unmet medical need for new-targeted therapies for use in Ewing sarcoma. In light of existing impediments to commercial drug discovery/development for orphan diseases such as Ewing sarcoma, there is a need for academic leadership in drug discovery for this disease indication. In this proposal, several innovative approaches will be used to identify and validate small-molecule inhibitors of EWS/FLI activity. These approaches circumvent many of the hurdles that have hindered the identification of therapies specifically targeting transcription factors.
1.1#Aims and goals specified in corresponding grant
Aim 1. Collaborate with MLPCN to implement a validated high-throughput screen to identify small molecule inhibitors of the EWS/FLI oncoprotein.
Aim 2. Employ GE-HTS as a secondary assay to validate hits for repression of EWS/FLI transcriptional activity.
Aim 3. Collaborate with MLPCN to develop and characterize chemical probes using a panel of validated tertiary assays.


Ewing sarcoma, transcription factor, chromosome translocation
Biological Relevance:

Over the last decade, the paradigm of cancer drug discovery has shifted to one largely focused on therapies directed at disease-specific targets. With greater tumor cell specificity, targeted therapies hold the promise of improved efficacy and decreased morbidity compared to conventional cytotoxic chemotherapy. The development of drugs targeting oncogenic kinases, such as HER2, BCR-ABL, EGFR, ALK, and B-RAF is exemplary of the potential clinical success with targeted therapies. While these results engender great hope, the majority of emerging proteins implicated in oncogenesis have been considered"undruggable." Aberrantly activated transcription factors, for example, are one group of refractory proteins which play a critical role in the development of most cancers. In some cancers, chromosomal translocations produce a mutant transcription factor, such as EWS/FLI in Ewing sarcoma, which directly alters the expression of genes responsible for transformation. In other cancers, activated signaling pathways result in ectopic activity of native transcription factors critical for cancer formation, such as MYC. Given their significant role in cancer, directly targeting transcription factors should be a successful antitumor strategy. However, with the exception of the nuclear hormone receptor family of transcription factors, transcription factor oncoproteins have been largely refractory to conventional drug discovery approaches. Many pediatric cancers, in principle, are ideally suited for the development of targeted transcription factor therapies because several of these diseases are causally linked to single genetically encoded oncogenes. Ewing sarcoma cells, for example, have a strict dependency on the EWS/FLI oncoprotein and are thus "oncogene-addicted" to ongoing EWS/FLI activity. While the EWS/FLI transcription factor rearrangement was discovered over 15 years ago, successful therapy targeting this transcription factor abnormality has yet to be developed, and new therapies for this disease are very much needed. The vast majority of children with metastastic Ewing sarcoma will relapse after multimodality therapy, and relapse is almost uniformly fatal. Moreover, even for children who are cured, long-term morbidity of cytotoxic treatment is significant. There remains an urgent unmet medical need for new-targeted therapies for use in Ewing sarcoma. In light of existing impediments to commercial drug discovery/development for orphan diseases such as Ewing sarcoma, there is a need for academic leadership in drug discovery for this disease indication.
Additional Information
Grant Number: DA034596-01

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