Safety, Tolerability, and Effects on Plasma and Cerebrospinal Fluid Amyloid-β After Inhibition of γ-Secretase

Siemers, Eric; Dean, Robert A.; Friedrich, Stuart; Ferguson-Sells, Lisa; Gonzales, Celedon; Farlow, Martin R.; May, Patrick C.

doi:10.1097/wnf.0b013e31805b7660

Cited by 144 publications

(134 citation statements)

References 23 publications

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…The initial decrease in plasma A␤ 40 levels at early time points after all doses and subsequent increases in plasma A␤ 40 levels at later time points are similar to what has been described in preclinical (Burton et al, 2008) and clinical (Siemers et al, 2005(Siemers et al, , 2007 studies with other GSIs. This effect on a pharmacodynamic biomarker has provided preliminary evidence for target engagement in humans, but additional studies of GSI-953 PK and pharmacodynamic parameters in human CSF are required to understand target engagement in the central nervous system.…”

Section: Discussionsupporting

confidence: 66%

Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease

Martone

Zhou²,

Atchison³

et al. 2009

J Pharmacol Exp Ther

148

124

View full text Add to dashboard Cite

The presenilin containing ␥-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. ␥-Secretase catalyzes the final step in the generation of A␤ 40 and A␤ 42 peptides from APP. Amyloid ␤-peptides (A␤ peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic A␤ peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide ␥-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits A␤ production with low nanomolar potency in cellular and cell-free assays of ␥-secretase function, and displaces a tritiated analog of GSI-953 from enriched ␥-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid A␤ levels, and a reversal of contextual fear-conditioning deficits that are correlated with A␤ load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dosedependent changes in plasma A␤ levels, confirming pharmacodynamic activity of GSI-953 in humans.This research was supported by Wyeth Research. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

show abstract

Section: Discussionsupporting

confidence: 66%

Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease

Martone

Zhou²,

Atchison³

et al. 2009

J Pharmacol Exp Ther

148

124

View full text Add to dashboard Cite

show abstract

“…Many researchers are carefully studying these molecules because they can be potentially effective in cancer and in the Alzheimer disease (18,26). Recently, the results of a phase I trial and of phase II trials (in Alzheimer disease) with the γ-secretase inhibitor LY450139 have been published (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Monticone

Biollo

Fabiano

et al. 2009

Molecular Cancer Research

View full text Add to dashboard Cite

γ-secretase inhibitors have been proposed as drugs able to kill cancer cells by targeting the NOTCH pathway. Here, we investigated two of such inhibitors, the Benzyloxicarbonyl-Leu-Leu-Nle-CHO (LLNle) and the N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), to assess whether they were effective in killing human glioblastoma tumor-initiating cells (GBM TIC) in vitro. We found that only LLNle was able at the micromolar range to induce the death of GBM TICs by apoptosis. To determine the cellular processes that were activated in GBM TICs by treatment with LLNle, we analyzed the amount of the NOTCH intracellular domain and the gene expression profiles following treatment with LLNle, DAPT, and DMSO (vehicle). We found that LLNIe, beside inhibiting the generation of the NOTCH intracellular domain, also induces proteasome inhibition, proteolytic stress, and mitotic arrest in these cells by repressing genes required for DNA synthesis and mitotic progression and by activating genes acting as mitotic inhibitors. DNA content flow cytometry clearly showed that cells treated with LLNle undergo arrest in the G 2 -M phases of the cell cycle. We also found that DAPT and L-685,458, another selective Notch inhibitor, were unable to kill GBM TICs, whereas lactacystin, a pure proteasome inhibitor, was effective although at a much less extent than LLNle. These data show that LLNle kills GBM TIC cells by inhibiting the proteasome activity. We suggest that LLNle, being able to target two relevant pathways for GBM TIC survival, may have a potential therapeutic value that deserves further investigation in animal models.

show abstract

“…For drug development purposes, it is necessary to identify an effect biomarker in an accessible compartment that can serve as a surrogate of A␤ modulation in the brain. To this end, CSF A␤ has been chosen (Siemers et al, 2007;Ereshefsky et al, 2008;Stone, 2009;Martenyi et al, 2010;Meredith et al, 2011) with the presumption that A␤ changes in CSF reflect the pharmacological activities in brain. To inform decision making based on CSF A␤ data from clinical trials, preclinical evaluation of the effect of a BACEi, GSI, or GSM on CSF A␤ has been routinely conducted (Barten et al, 2005;Sankaranarayanan et al, 2009;Hawkins et al, 2011;Lu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal Fluid Amyloid-β (Aβ) as an Effect Biomarker for Brain Aβ Lowering Verified by Quantitative Preclinical Analyses

Lu¹,

Riddell²,

Hajós‐Korcsok³

et al. 2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Reducing the generation of amyloid-␤ (A␤) in the brain via inhibition of ␤-secretase or inhibition/modulation of ␥-secretase has been pursued as a potential disease-modifying treatment for Alzheimer's disease. For the discovery and development of ␤-secretase inhibitors (BACEi), ␥-secretase inhibitors (GSI), and ␥-secretase modulators (GSM), A␤ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for A␤ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF A␤ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF A␤ lowering is related to that for brain A␤ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF A␤ as an effect biomarker for brain A␤ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of A␤ lowering in the brain.

show abstract

Safety, Tolerability, and Effects on Plasma and Cerebrospinal Fluid Amyloid-β After Inhibition of γ-Secretase

Abstract: These data show that single doses of LY450139 up to 140 mg are accompanied by a dose-dependent plasma Abeta response. No response in CSF Abeta was apparent 4 hours after dosing.

Cited by 144 publications

References 23 publications

Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease

Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease

z-Leucinyl-Leucinyl-Norleucinal Induces Apoptosis of Human Glioblastoma Tumor–Initiating Cells by Proteasome Inhibition and Mitotic Arrest Response

Cerebrospinal Fluid Amyloid-β (Aβ) as an Effect Biomarker for Brain Aβ Lowering Verified by Quantitative Preclinical Analyses

Contact Info

Product

Resources

About