Bookmark and Share
BioAssay: AID 652276

Discovery and structure-activity relationship of BMP Inhibitors, Secondary in-citro ALK2 Assay

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 ..
_
   
 Tested Compounds
 Tested Compounds
All(10)
 
 
Active(9)
 
 
Inactive(1)
 
 
 Tested Substances
 Tested Substances
All(10)
 
 
Active(9)
 
 
Inactive(1)
 
 
 Related BioAssays
 Related BioAssays
AID: 652276
Data Source: Vanderbilt Specialized Chemistry Center (In vitro ALK2 kinase inhibition assay)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2013-04-04
Hold-until Date: 2014-04-04
Modify Date: 2014-04-07

Data Table ( Complete ):           Active    All
Target
Sequence: ACVR1 protein [Homo sapiens]
Description ..   

Gene:ACVR1     Conserved Domain     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 9
Depositor Specified Assays
AIDNameTypeComment
652288Developing potent and selective BMP inhibitors as translational tools to develop future therapiessummary
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. The desired attributes of the proposed small molecule probe will be high potency (low IC50) in inhibiting BMP-dependent signaling in reporter cells, and inhibiting the type-I BMP receptor ALK2 in in vitro kinase assays using the purified enzyme (Reaction Biology).



Protocol
In vitrokinase activity of purified ALK2 on target peptide will be measure in the presence of various concentrations of compounds.





Positive criterion will be >50% inhibition of ALK2 activity at 1mM. Negative criterion will be <50% inhibition of ALK2 activity at 1mM. This assay will also establish which compound has the greatestin vitropotency against ALK2.














Result Definitions
Show more
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1IC50_uM*IC50FloatμM
2CategoryHow the compound is classified as, Inhibitor or InactiveString
3Activity_100_uM (100μM**)See ProtocolFloat
4Activity_33.3_uM (33.3μM**)See ProtocolFloat
5Activity_11.1_uM (11.1μM**)See ProtocolFloat
6Acitivity_3.7_uM (3.7μM**)See ProtocolFloat
7Activity_1.23_uM (1.23μM**)See ProtocolFloat
8Activity_0.412_uM (0.412μM**)See ProtocolFloat
9Activity_0.137_uM (0.137μM**)See ProtocolFloat
10Activity_0.0457_uM (0.0457μM**)See ProtocolFloat
11Activity_0.0152_uM (0.0152μM**)See ProtocolFloat
12Activity_0.00508_uM (0.00509μM**)See ProtocolFloat

* Activity Concentration. ** Test Concentration.
Additional Information
Grant Number: R01HL104040-02

Data Table (Concise)
Classification
PageFrom: