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BioAssay: AID 652284

Discovery and structure-activity relationship of BMP Inhibitors, in-vivo SAR, zebrafish embryo 24-well plate

Because the heart has negligible intrinsic capacity to regenerate new tissues to replace those lost to injury, there is currently no definitive heart failure treatment, other than organ transplantation. Recent studies have introduced the prospect of replacing damaged heart tissues with healthy cardiomyocytes derived from pluripotent stem cells. However, realizing the full therapeutic potential of more ..
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 Tested Compounds
 Tested Compounds
All(7)
 
 
Active(5)
 
 
Inactive(2)
 
 
 Tested Substances
 Tested Substances
All(7)
 
 
Active(5)
 
 
Inactive(2)
 
 
AID: 652284
Data Source: Vanderbilt Specialized Chemistry Center (In vivoSAR (structure activity relationship) study BMP inhib..)
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2013-04-05
Hold-until Date: 2014-04-05
Modify Date: 2014-04-07

Data Table ( Complete ):           View Active Data    View All Data
BioActive Compounds: 5
Related Experiments
AIDNameTypeProbeComment
652288Developing potent and selective BMP inhibitors as translational tools to develop future therapiesSummary depositor-specified cross reference
652276Discovery and structure-activity relationship of BMP Inhibitors, Secondary in-citro ALK2 AssayConfirmatory same project related to Summary assay
652282Discovery and structure-activity relationship of BMP InhibitorsConfirmatory1 same project related to Summary assay
686923In vitrocounter assay of key BMP4 InhibitorsOther same project related to Summary assay
686924ML347 Eurofin Panel Assay for BMP Inhibitor (Probe Compound)Other same project related to Summary assay
Description:
Assay Provider: Charles Hong

Assay Provider Affiliation: Vanderbilt University

Because the heart has negligible intrinsic capacity to regenerate new tissues to replace those lost to injury, there is currently no definitive heart failure treatment, other than organ transplantation. Recent studies have introduced the prospect of replacing damaged heart tissues with healthy cardiomyocytes derived from pluripotent stem cells. However, realizing the full therapeutic potential of stem cells faces numerous hurdles, including the potential for tumor formation, a low rate of cardiomyocyte formation, and an inadequate mechanistic understanding of cardiomyogenesis. Additionally, translational efforts are hampered by a lack of pharmaceutical agents to boost therapeutic effects of stem cells. Dorsomorphin, the first known small molecule inhibitor of the bone morphogenetic protein (BMP) signaling, is one of the most potent chemical inducers of cardiomyogenesis in mouse embryonic stem (ES) cells. Dorsomorphin treatment during the initial 24 to 48 hours of ES cell differentiation was sufficient for robust cardiomyocyte induction. Strikingly, the massive cardiac induction occurs apparently in the absence of mesoderm induction and at the expense of other mesoderm-derived lineages, including endothelial, smooth muscle and hematopoietic lineages. From these results, we hypothesize that atimely BMP signal inhibition commits the primitive multipotent progenitor cells toward the cardiomyocyte development. The aim is to develop potent and selective BMP inhibitors with excellent pharmaceutical properties (no cellular toxicity, high solubility, limited off-target activity) for use in directed differentiation of pluripotent stem cell toward cardiac development. Here, the Assessment of specific perturbations in embryonic dorsoventral patterning without additional toxicity or nonspecific defects is performed.


Protocol
3-hour old zebrafish embryos will be arrayed in 24-well culture plates, and compounds delivered at various concentrations from 0.1mM to 100mM. 20 embryos will be tested for each condition. At 24-48 hours, embryos will be examined for specific perturbations in embryonic dorsoventral pattern, or nonspecific lethality or developmental delay. Compounds that dorsalize the embryonic pattern at lowest tested concentrations are deemed most potent, while compounds that only dorsalize and do not cause additional defects or nonspecific toxicities at the highest tested concentrations will be deemed most selective.
The in vivo assay is very robust with negligible false positive rate (<0.1%). Positive criterion is dorsalization of 2 or more embryos out of 20 tested at concentrations tested (at EC50, 10 embryos out of 20 tested will be dorsalized). Negative criterion is 1 or fewer embryos out of 20 tested. Compounds with EC50< 2.5mM on in vivo testing will be pursued further.
Categorized Comment - additional comments and annotations
From PubChem:
Assay Test Type: In vivo
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1CategoryHow the compound is classified as, Inhibitor or InactiveString

Data Table (Concise)
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