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BioAssay: AID 624046

Reaction Biology data for inhibitors of DYRK1B: Probe SAR

Alternative splicing of pre-mRNAs plays a major role in the regulation of eukaryotic gene expression. Alternative splicing is now thought to be one of the primary reasons for the complexity of higher organisms leading to an average of three protein isoforms per gene. Aberrant splicing can lead to a number of diseases and is known to play a role in rare genetic diseases such as progeria syndrome. more ..
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 Tested Compounds
 Tested Compounds
All(32)
 
 
Active(27)
 
 
Inactive(4)
 
 
Inconclusive(1)
 
 
 Tested Substances
 Tested Substances
All(32)
 
 
Active(27)
 
 
Inactive(4)
 
 
Inconclusive(1)
 
 
AID: 624046
Data Source: NCGC (CLK006)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-04-10
Hold-until Date: 2013-04-08
Modify Date: 2013-04-10

Data Table ( Complete ):           Active    All
Target
BioActive Compounds: 27
Depositor Specified Assays
AIDNameTypeComment
1997qHTS for Inhibitors of CDC-like Kinase 4: Summarysummary
Description:
Alternative splicing of pre-mRNAs plays a major role in the regulation of eukaryotic gene expression. Alternative splicing is now thought to be one of the primary reasons for the complexity of higher organisms leading to an average of three protein isoforms per gene. Aberrant splicing can lead to a number of diseases and is known to play a role in rare genetic diseases such as progeria syndrome. Hutchinson-Gilford Progeria Syndrome (HGPS) is a pediatric premature aging disease caused by a spontaneous mutation in the lamin A/C (LMNA) gene due to a single point mutation in the lamin A gene effecting 1 in 4 million people.

To identify both specific splicing modulators of the lamin A gene as well as general splicing modulators, a cell-based HTS assay was developed using a minigene reporter system (AIDs, 1459 & 1487). A pyrimidine series showed activity as an inhibitor of aberrant splicing using the minigene reporter system (AID 1498). A preliminary kinase profile of this compound showed activity in splicing related kinases belonging to the CDC-like kinase (Clk) family. This AID summarizes the characterization of lead compounds in Dyrk1b.

NIH Molecular Libraries Probe Production Centers Network [MLPCN]
NIH Chemical Genomics Center [NCGC]

MLPCN Grant: MH084827
Assay Submitter (PI): Tom Misteli
Protocol
Compound IC50s were determined at Reaction Biology (http://www.reactionbiology.com) with ten concentration points starting at 10 uM in the assay using a 3-fold dilution series. The control compound staurosporine was also tested in the 10-dose IC50 mode with the same 3-fold serial dilution, again starting at 10 uM. All kinase reactions were performed using 10 uM ATP in the assay. 100% activity was taken from kinase reactions with DMSO alone (the vehicle used for compound stock solutions).
Comment
Compound Ranking:

1. Compounds are first classified as having full titration curves, partial modulation, partial curve (weaker actives), single point activity (at highest concentration only), or inactive. See data field "Curve Description". For this assay, apparent inhibitors are ranked higher than compounds that showed apparent activation.
2. For all inactive compounds, PUBCHEM_ACTIVITY_SCORE is 0. For all active compounds, a score range was given for each curve class type given above. Active compounds have PUBCHEM_ACTIVITY_SCORE between 40 and 100. Inconclusive compounds have PUBCHEM_ACTIVITY_SCORE between 1 and 39. Fit_LogAC50 was used for determining relative score and was scaled to each curve class' score range.
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1PhenotypeIndicates type of activity observed: inhibitor, activator, fluorescent, cytotoxic, inactive, or inconclusive.String
2Potency*Concentration at which compound exhibits half-maximal efficacy, AC50. Extrapolated AC50s also include the highest efficacy observed and the concentration of compound at which it was observed.FloatμM
3EfficacyMaximal efficacy of compound, reported as a percentage of control. These values are estimated based on fits of the Hill equation to the dose-response curves.Float%
4Analysis CommentAnnotation/notes on a particular compound's data or its analysis.String
5Activity_ScoreActivity score.Integer
6Curve_DescriptionA description of dose-response curve quality. A complete curve has two observed asymptotes; a partial curve may not have attained its second asymptote at the highest concentration tested. High efficacy curves exhibit efficacy greater than 80% of control. Partial efficacies are statistically significant, but below 80% of control.String
7Fit_LogAC50The logarithm of the AC50 from a fit of the data to the Hill equation (calculated based on Molar Units).Float
8Fit_HillSlopeThe Hill slope from a fit of the data to the Hill equation.Float
9Fit_R2R^2 fit value of the curve. Closer to 1.0 equates to better Hill equation fit.Float
10Fit_InfiniteActivityThe asymptotic efficacy from a fit of the data to the Hill equation.Float%
11Fit_ZeroActivityEfficacy at zero concentration of compound from a fit of the data to the Hill equation.Float%
12Fit_CurveClassNumerical encoding of curve description for the fitted Hill equation.Float
13Excluded_PointsWhich dose-response titration points were excluded from analysis based on outlier analysis. Each number represents whether a titration point was (1) or was not (0) excluded, for the titration series going from smallest to highest compound concentrations.String
14Max_ResponseMaximum activity observed for compound (usually at highest concentration tested).Float%
15Activity at 0.0005080000 uM (0.000508μM**)% Activity at given concentration.Float%
16Activity at 0.00102 uM (0.00102μM**)% Activity at given concentration.Float%
17Activity at 0.00152 uM (0.00152μM**)% Activity at given concentration.Float%
18Activity at 0.00305 uM (0.00305μM**)% Activity at given concentration.Float%
19Activity at 0.00457 uM (0.00457μM**)% Activity at given concentration.Float%
20Activity at 0.00914 uM (0.00914μM**)% Activity at given concentration.Float%
21Activity at 0.014 uM (0.0137μM**)% Activity at given concentration.Float%
22Activity at 0.027 uM (0.0274μM**)% Activity at given concentration.Float%
23Activity at 0.041 uM (0.0412μM**)% Activity at given concentration.Float%
24Activity at 0.120 uM (0.120285μM**)% Activity at given concentration.Float%
25Activity at 0.247 uM (0.247μM**)% Activity at given concentration.Float%
26Activity at 0.370 uM (0.37μM**)% Activity at given concentration.Float%
27Activity at 0.741 uM (0.741μM**)% Activity at given concentration.Float%
28Activity at 1.110 uM (1.11μM**)% Activity at given concentration.Float%
29Activity at 2.220 uM (2.22μM**)% Activity at given concentration.Float%
30Activity at 3.330 uM (3.33μM**)% Activity at given concentration.Float%
31Activity at 6.670 uM (6.67μM**)% Activity at given concentration.Float%
32Activity at 10.000 uM (10μM**)% Activity at given concentration.Float%
33Activity at 20.00 uM (20μM**)% Activity at given concentration.Float%
34Compound QCNCGC designation for data stage: 'qHTS', 'qHTS Verification', 'Secondary Profiling'String

* Activity Concentration. ** Test Concentration.
Additional Information
Grant Number: MH084827

Data Table (Concise)
Classification
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