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ML013 : CREB1 (cAMP Response Element Binding Protein) Potentiator

ML013

ML013

Target Name

cAMP Response Element Binding Protein

Target Alias

CREB1

Target Class

Transcription Factor

Mechanism of Action

Potentiator of CREB1

Biological / Disease Relevance

CRE, CREB signaling pathway

Cell-based activity (CHO CRE-B-lactamase)
AC50
0.0158 uM
Cell-based activity (HEK293 CRE-luciferase)
AC50
0.0794 uM
Inactive Control
Available

Target Information

The cyclic response element-binding proteins (CREB) are a class of transcription factors that bind to selected cAMP response element (CRE) segments of DNA and catalyze the transcription of these genetic sequences. Abnormalities in the functioning of CREB signaling has been linked to the development and progression of Huntington’s Disease, Tubinstein-Taybi syndrome and has been linked to several cancers in addition to its well characterized role in the activation of neurons during learning with changes in gene expression required for long-term memory formation.

In an effort to comprehensively explore the entire signal transduction pathway, a cell based screen was established, optimized and completed. A cell-based assay developed by Invitrogen Corp3 using a beta-lactamase reporter-gene under control of cAMP responsive element was used to measure the potentiation of CRE signaling. Library compounds were measured for their ability to modulate positively the action of EC10 NKH 477, a water soluble forskolin, on reporter gene activity. Compounds were screened in a titration series in 1536-well format. Positive and negative modulators were identified based on the AC50 values derived from the screening data.

Properties

ML013

NCGC00067819

Physical & chemical properties
Molecular Weight 346.4 g/mol
Molecular Formula C19H14N4OS
cLogP 4.4
PSA 92.9 A^2
Storage
Solubility
CAS Number

SMILES:
CC1=NC2=C(OC3=CC=CC=C32)C(SCC4=NC5=CC=CC=C5N4)=N1

InChI:
InChI=1S/C19H14N4OS/c1-11-20-17-12-6-2-5-9-15(12)24-18(17)19(21-11)25-10-16-22-13-7-3-4-8-14(13)23-16/h2-9H,10H2,1H3,(H,22,23)

InChIKey:
FSHFRKKIBVABAJ-UHFFFAOYSA-N

Activity

Summary activity statement /

ML013 (SID 863038, CID 664279, NCGC00067819) is observed to be a potent  potentiator of CRE / CREB signaling pathway with an AC50 of 15.8 nM in primary screen and 79 nM in confirmatory study.

Cell-based activity - HEK293 CRE reporter gene assay

Summary /

Concentration response curve of ML013 (SID 863038) in confirmatory study

Confirmation studies: Approximately 100 compounds were selected and retested in the original CHO CRE-beta-lactamase assay. The confimation rate was 95% compared to primary qHTS. Next, these compounds were tested in HEK293 cells. The concordance rate is 80% between these two CRE reported gene assays. Among these compounds, NCGC00067819-01 (SID: 863038) is most potent compound with AC50 of 79 nM in confirmation study and 16 nM in primary screening.

 

References

  1. Identification of compounds that potentiate CREB signaling as possible enhancers of long-term memory
  2. Cell signaling CRE-BLA (Fsk stim)
  3. Confirmation Concentration-Response Assay for Cell signaling CRE-BLA (Fsk stim)
  4. Confirmation Concentration-Response Assay for Cell signaling CRE-BLA (Fsk stim) - HEK293 CREB Luciferase
  5. Cell Viability - CRE-beta lactamase CHO cell - 40 hr assay
  6. Cell Viability - CRE-beta lactamase CHO cell - 24 hr assay