Abstract | BACKGROUND AND PURPOSE: EXPERIMENTAL APPROACH: We screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity. KEY RESULTS: Among 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In glial fibrillary acidic protein-gp120 transgenic (tg) mice, sunitinib reduced levels of pCDK5, p35/p25 and phosphorylated tau protein, along with amelioration of the neurodegenerative pathology. CONCLUSIONS AND IMPLICATIONS:
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Authors | Wolf Wrasidlo, Leslie A Crews, Igor F Tsigelny, Emily Stocking, Valentina L Kouznetsova, Diana Price, Amy Paulino, Tania Gonzales, Cassia R Overk, Christina Patrick, Edward Rockenstein, Eliezer Masliah |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 171
Issue 24
Pg. 5757-73
(Dec 2014)
ISSN: 1476-5381 [Electronic] England |
PMID | 25117211
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2014 The British Pharmacological Society. |
Chemical References |
- Antineoplastic Agents
- Flavonoids
- HIV Envelope Protein gp120
- Indoles
- Neuroprotective Agents
- Protein Kinase Inhibitors
- Purines
- Pyrimidines
- Pyrroles
- Quinazolines
- Thiazoles
- Roscovitine
- Lapatinib
- Erlotinib Hydrochloride
- Cyclin-Dependent Kinase 5
- Dasatinib
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
- Sunitinib
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Topics |
- AIDS Dementia Complex
- Animals
- Antineoplastic Agents
(pharmacology)
- Cyclin-Dependent Kinase 5
(drug effects)
- Dasatinib
- Erlotinib Hydrochloride
- Flavonoids
(pharmacology)
- HIV Envelope Protein gp120
(genetics, toxicity)
- In Vitro Techniques
- Indoles
(pharmacology)
- Lapatinib
- Mice
- Mice, Transgenic
- Neurodegenerative Diseases
- Neurons
(drug effects)
- Neuroprotective Agents
(pharmacology)
- Protein Kinase Inhibitors
(pharmacology)
- Purines
(pharmacology)
- Pyrimidines
(pharmacology)
- Pyrroles
(pharmacology)
- Quinazolines
(pharmacology)
- Rats
- Roscovitine
- Sunitinib
- Thiazoles
(pharmacology)
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