6 research outputs found
Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418
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 (K i = 38 nM). AR-A014418 does not significantly inhibit cdk2 or cdk5 (IC50 > 100 ÎŒM) or 26 other kinases demonstrating high specificity for GSK3. We report the co-crystallization of AR-A014418 with the GSK3ÎČ 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 ÎČ-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.Supported by grants from the Comunidad de Madrid, the Fundacion âLa Caixa,â the Lilly Foundation, the Spanish Comision Interministerial de Ciencia y Tecnologia, and an institutional grant from the Fundacion Ramon Areces.Peer reviewe
Discovery of Novel Potent and Highly Selective Glycogen Synthase Kinase-3ÎČ (GSK3ÎČ) Inhibitors for Alzheimerâs Disease: Design, Synthesis, and Characterization of Pyrazines
Glycogen synthase kinase-3ÎČ, also called tau phosphorylating
kinase, is a proline-directed serine/threonine kinase which was originally
identified due to its role in glycogen metabolism. Active forms of
GSK3ÎČ localize to pretangle pathology including dystrophic neuritis
and neurofibrillary tangles in Alzheimerâs disease (AD) brain.
By using a high throughput screening (HTS) approach to search for
new chemical series and cocrystallization of key analogues to guide
the optimization and synthesis of our pyrazine series, we have developed
highly potent and selective inhibitors showing cellular efficacy and
bloodâbrain barrier penetrance. The inhibitors are suitable
for in vivo efficacy testing and may serve as a new treatment strategy
for Alzheimerâs disease
Substituted 7âAmino-5-thio-thiazolo[4,5â<i>d</i>]pyrimidines as Potent and Selective Antagonists of the Fractalkine Receptor (CX<sub>3</sub>CR1)
We have developed two parallel series,
A and B, of CX<sub>3</sub>CR1 antagonists for the treatment of multiple
sclerosis. By modifying
the substituents on the 7-amino-5-thio-thiazoloÂ[4,5-<i>d</i>]Âpyrimidine core structure, we were able to achieve compounds with
high selectivity for CX<sub>3</sub>CR1 over the closely related CXCR2
receptor. The structureâactivity relationships showed that
a leucinol moiety attached to the core-structure in the 7-position
together with α-methyl branched benzyl derivatives in the 5-position
displayed promising affinity, and selectivity as well as physicochemical
properties, as exemplified by compounds <b>18a</b> and <b>24h</b>. We show the preparation of the first potent and selective
orally available CX<sub>3</sub>CR1 antagonists