Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

Mayer, Scott C.; Kreft, Anthony F.; Harrison, Boyd L.; Abou‐Gharbia, Magid; Antane, Madelene; Aschmies, Suzan; Atchison, Kevin; Chlenov, Michael; Cole, Derek C.; Comery, Thomas A.; Diamantidis, George; Ellingboe, John W.; Fan, Kristi; Galante, Rocco; Gonzales, Cathleen; Ho, Douglas M.; Hoke, M.; Hu, Yun; Huryn, Donna M.; Jain, Uday; Jin, Mei; Kremer, Kenneth; Kubrak, Dennis; Lin, Melissa; Lu, Peter J.; Magolda, R. L.; Martone, Robert; Moore, William; Oganesian, Aram; Pangalos, Menelas N.; Porte, Annalena La; Reinhart, Peter H.; Resnick, Lauren B.; Riddell, David; Sonnenberg-Reines, June; Stock, Joseph R.; Sun, Shaiu-Ching; Wagner, Erik; Wang, Ting; Woller, Kevin R.; Xu, Zheng; Zaleska, Margaret M.; Zeldis, Joseph; Zhang, Minsheng; Zhou, Hua; Jacobsen, J. Steven

doi:10.1021/jm801252w

Cited by 101 publications

(71 citation statements)

References 28 publications

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“…This may reflect subtle variations between the cellular and in vitro conformations of ␥-secretase. Nevertheless, the cell-based studies confirmed that CS-1 maintains a preference for inhibition of the ␥-secretase mediated production of A␤42 over A␤40 or A␤38, which is distinct from previously reported GSMs (17) and inhibitors (14,15,18).…”

Section: Di-coumarin Compounds Are Selective Gsis In Cellssupporting

confidence: 41%

“…Subsequent studies have shown that these GSMs alter ␥-secretase cleavage preference by binding directly to the APP substrate (13). Other compounds that target ␥-secretase and preferentially inhibit A␤40 and A␤42 production over Notch1 processing have been reported (14,15), although the precise action mechanism of these molecules has not been established. Therefore, it is critical to develop a better understanding of the molecular basis of ␥-secretase specificity to facilitate the development of selective GSIs for the treatment of AD and other human disorders.…”

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confidence: 99%

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Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Shelton

Zhu²,

Chau

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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␥-Secretase cleaves multiple substrates within the transmembrane domain that include the amyloid precursor protein as well as the Notch family of receptors. These substrates are associated with Alzheimer disease and cancer. Despite extensive investigation of this protease, little is known regarding the regulation of ␥-secretase specificity. To discover selective inhibitors for drug development and for probing the mechanisms of ␥-secretase specificity, we screened chemical libraries and consequently developed a di-coumarin family of inhibitors that preferentially inhibit ␥-secretase-mediated production of A␤42 over other cleavage activities. These coumarin dimerbased compounds interact with ␥-secretase by binding to an allosteric site. By developing a multiple photo-affinity probe approach, we demonstrate that this allosteric binding causes a conformational change within the active site of ␥-secretase at the S2 and S1 sub-sites that leads to selective inhibition of A␤42. In conclusion, by using these di-coumarin compounds, we reveal a mechanism by which ␥-secretase specificity is regulated and provide insights into the molecular basis by which familial presenilin mutations may affect the active site and specificity of ␥-secretase. Furthermore, this class of selective inhibitors provides the basis for development of Alzheimer disease therapeutic agents. affinity labeling ͉ Alzheimer disease ͉ allosteric regulation ͉ di-coumarin ␥ -Secretase is a multi-protein membrane-bound complex that is currently at the front line of basic and translational research. It is composed of at least 4 proteins that include presenilin, nicastrin, Aph-1, and Pen-2 (1). Presenilin is believed to contain the active site of ␥-secretase (2-4). It represents a novel class of protease that catalyzes peptide bond hydrolysis within the transmembrane hydrophobic environment and plays an essential role in a newly emerged signaling pathway known as regulated intramembrane proteolysis (5). ␥-Secretase cleaves a variety of type I membrane proteins that include the amyloid precursor protein (APP) and the Notch family of proteins despite limited primary sequence homology across targeted substrates (6). Elucidation of the mechanisms that control the specificity of ␥-secretase for these substrates has been hindered by technical difficulties associated with intramembrane enzymology. Determining the factors that contribute to ␥-secretase specificity is critical to understanding the biology of this unique protease and targeting it for therapeutic purposes.␥-Secretase has become an appealing drug target for Alzheimer disease (AD) and cancer because of its central role in the processing of APP and Notch (6). ␥-Secretase cleaves APP to generate neurotoxic A␤ peptides, ranging from 37 to 46 aa in length (7). Among them, A␤40 and A␤42 have been extensively investigated for their association with AD (7). Additionally, diseasecausing familial AD mutations within APP, presenilin-1 (PS-1), and presenilin-2 (PS-2) proteins result in an increase in the ratio of A␤42...

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Section: Di-coumarin Compounds Are Selective Gsis In Cellssupporting

confidence: 41%

mentioning

confidence: 99%

Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Shelton

Zhu²,

Chau

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…5 Both compounds were >200-fold more potent than the lead compound 1 and showed improved selectivity against Notch, an important protein involved in cell development and differentiation. Unfortunately, these compounds displayed poor stability in human microsomes (t 1/2 < 10 min).…”

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confidence: 98%

“…while maintaining potency against Aβ production and selectivity versus Notch. 5 Begacestat was further characterized in a number of preclinical assays and has been dosed in healthy human volunteers. 6 As was reported in the lead optimization paper, 5 begascestat was shown to inhibit Aβ production in the low nanomolar range (Aβ 40 EC 50 = 14.8 nM and Aβ 42 EC 50 = 12.4 nM) in both cellular and cell-free assays.…”

mentioning

confidence: 99%

“…5 Begacestat was further characterized in a number of preclinical assays and has been dosed in healthy human volunteers. 6 As was reported in the lead optimization paper, 5 begascestat was shown to inhibit Aβ production in the low nanomolar range (Aβ 40 EC 50 = 14.8 nM and Aβ 42 EC 50 = 12.4 nM) in both cellular and cell-free assays. The group also reported on a close analogue of GSI-953 (WAY-210952, the (R)-isomer), which was shown to have much reduced potency (>10 μM) for Aβ production inhibition.…”

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confidence: 99%

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ACS Chemical Neuroscience Molecule Spotlight on Begacestat (GSI-953)

Hopkins

2012

ACS Chem. Neurosci.

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Approaches to Amyloid Therapies for the Treatment of Alzheimer's Disease

Robichaud

Kim

Jacobsen

2010

Burger's Medicinal Chemistry and Drug Discovery

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Recognized as the most common of the neurodegenerative disorders, Alzheimer's disease (AD) affects greater than 18 million people worldwide and is predicted to become the largest socioeconomic burden of the twenty‐first century. The underlying mechanism of Alzheimer's disease is as yet unknown, but the growing body of pathophysiologic evidence is beginning to point to two main causes, the formation of β‐amyloid plaques and neurofibrillary tangles. This review will cover approaches to disease modification that are based on the amyloid hypothesis; that being, the prevention of the accumulation, aggregation, and deposition of β‐amyloid peptide (Aβ) monomers, leading first to multiple oligomeric species and then to fibrils and ultimately senile plaques, is the center of focus for an approach to disease modification. There is a wealth of evidence to implicate this peptide and its subsequent aggregation in the etiology of the disease and approaches, both small molecule and biopharmaceutical, to prevent its accumulation have been the subject of much research. The vast majority of this research over the last decade has been, and continues to be, focused on these disease‐modifying, antiamyloidogenic approaches to AD. It is this subject, and the various approaches, past and present to amelioration of AD through the various agents being explored, that will be the focus of this chapter.

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Discovery of Begacestat, a Notch-1-Sparing γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease

Cited by 101 publications

References 28 publications

Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Modulation of γ-secretase specificity using small molecule allosteric inhibitors

ACS Chemical Neuroscience Molecule Spotlight on Begacestat (GSI-953)

Approaches to Amyloid Therapies for the Treatment of Alzheimer's Disease

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