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Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418
Ratan V. Bhat, Yafeng Xue, Stefan von Berg, Sven Hellberg, Mats Ormö, Yvonne Nilsson, Ann‐Cathrin Radesäter, Eva Jerning et al.. Journal of Biological Chemistry, 2003-11-01
Topic: Disease mechanisms in lab and animal studies
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. We report the characterization of a GSK3 inhibitor, AR-A014418, which inhibits GSK3 (IC50 = 104 +/- 27 nM), in an ATP-competitive manner (Ki = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3beta protein and provide a description of the interactions within the ATP pocket, as well as an understanding of the structural basis for the selectivity of AR-A014418. AR-A014418 inhibits tau phosphorylation at a GSK3-specific site (Ser-396) in cells stably expressing human four-repeat tau protein. AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. Furthermore, AR-A014418 inhibits neurodegeneration mediated by beta-amyloid peptide in hippocampal slices. AR-A014418 may thus have important applications as a tool to elucidate the role of GSK3 in cellular signaling and possibly in Alzheimer's disease. AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.
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APA 7th
Bhat, R. V., Xue, Y., von Berg, S., Hellberg, S., Ormö, M., Nilsson, Y., et al. (2003). Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m306268200
Vancouver
Bhat RV, Xue Y, von Berg S, Hellberg S, Ormö M, Nilsson Y, et al. Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418. Journal of Biological Chemistry. 2003. doi:10.1074/jbc.m306268200. PMID: 12928438.
BibTeX
@article{bhat2003-12928438,
author = {Bhat, Ratan V. and Xue, Yafeng and von Berg, Stefan and Hellberg, Sven and Ormö, Mats and Nilsson, Yvonne and Radesäter, Ann‐Cathrin and Jerning, Eva and others},
title = {{Structural Insights and Biological Effects of Glycogen Synthase Kinase 3-specific Inhibitor AR-A014418}},
journal = {Journal of Biological Chemistry},
year = {2003},
doi = {10.1074/jbc.m306268200},
pmid = {12928438},
url = {https://doi.org/10.1074/jbc.m306268200}
}
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Key findings
- AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 microM) or 26 other kinases demonstrating high specificity for GSK3.
- AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5.
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Study details
- Evidence strengthLow
How this study scored 40/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 23 of the 58 points we could judge it on, which is 40 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Biological Chemistry) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2003 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 12928438) |
| Free to read | 2 / 2 | Free to read |
| Points | 23 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 23 of the 58 points we could judge it on is 40 out of 100. |
| Total | 40 / 100 | — |
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