Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies

Selnick, Harold G.; Hess, J. Fred; Tang, Cuyue; Liu, Kun; Schachter, Joel B.; Ballard, Jeanine; Marcus, Jacob; Klein, Daniel; Wang, Xiaohai; Pearson, Michelle; Savage, Mary J.; Kaul, Ramesh; Li, Tong‐Shuang; Vocadlo, David J.; Zhou, Yuanxi; Zhu, Yingdan; Mu, Changwei; Wang, Yaode; Wei, Zhongyong; Bai, Chang; Duffy, Joseph; McEachern, Ernest J.

doi:10.1021/acs.jmedchem.9b01090

Cited by 102 publications

(100 citation statements)

References 40 publications

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“…In Vitro Characterization of MK-8719. MK-8719 was initially identified as a novel OGA inhibitor with excellent brain permeability (Selnick et al, 2019). The functional activity of MK-8719 against human, rat, and dog OGA was evaluated using fluorescent intensity assays with 2 mM 4methylumbelliferyl N-acetyl-b-D-glucosaminide dihydrate as a substrate.…”

Section: Resultsmentioning

confidence: 99%

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MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy

Wang¹,

Li²,

Marcus³

et al. 2020

J Pharmacol Exp Ther

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Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding enzymes from mouse, rat, and dog. In vivo, oral administration of MK-8719 elevates brain and peripheral blood mononuclear cell O-GlcNAc levels in a dose-dependent manner. In addition, positron emission tomography imaging studies demonstrate robust target engagement of MK-8719 in the brains of rats and rTg4510 mice. In the rTg4510 mouse model of human tauopathy, MK-8719 significantly increases brain O-GlcNAc levels and reduces pathologic tau. The reduction in tau pathology in rTg4510 mice is accompanied by attenuation of brain atrophy, including reduction of forebrain volume loss as revealed by volumetric magnetic resonance imaging analysis. These findings suggest that OGA inhibition may reduce tau pathology in tauopathies. However, since hundreds of O-GlcNAcylated proteins may be influenced by OGA inhibition, it will be critical to understand the physiologic and toxicological consequences of chronic O-GlcNAc elevation in vivo. SIGNIFICANCE STATEMENT MK-8719 is a novel, selective, and potent O-linked N-acetylglucosamine (O-GlcNAc)-ase (OGA) inhibitor that inhibits OGA enzyme activity across multiple species with comparable in vitro potency. In vivo, MK-8719 elevates brain O-GlcNAc levels, reduces pathological tau, and ameliorates brain atrophy in the rTg4510 mouse model of tauopathy. These findings indicate that OGA inhibition may be a promising therapeutic strategy for the treatment of Alzheimer disease and other tauopathies.

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Section: Resultsmentioning

confidence: 99%

“…Drug Administration. MK-8719 was prepared by Merck & Co., Inc., as described previously (Selnick et al, 2019). MK-8719 was administered either by oral gavage (5 ml/kg) or through in-diet dosing as described in Hastings et al (2017).…”

Section: Methodsmentioning

confidence: 99%

MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy

Wang¹,

Li²,

Marcus³

et al. 2020

J Pharmacol Exp Ther

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“…The posttranslational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) inhibits protein aggregation in multiple neurodegenerative diseases [72]. An oral inhibitor of O-GlcNAcase reduces tauopathy in rTg4510 mice [73] and has entered clinical development for progressive supranuclear palsy [74,75]. It is difficult to evaluate the relative efficacy of the small molecules targeting tau pathways without the performance of simultaneous studies in the same animal models using the same methodology.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

Davidowitz

Krishnamurthy

Lopez

et al. 2020

JAD

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Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.

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“…Additionally, O-GlcNAcylation inhibited the aggregation of an aggressive α-syn mutant. Interestingly, MK-8719, a CNS penetrant O-GlcNAcase inhibitor towards tauopathies, has been advanced to phase 1 clinical trial [162]. This molecule could also represent a promising anti-aggregative therapeutic target towards α-syn in PD.…”

Section: O-glcnacylationmentioning

confidence: 99%

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

et al. 2020

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Parkinson’s Disease (PD) is characterized both by the loss of dopaminergic neurons in the substantia nigra and the presence of cytoplasmic inclusions called Lewy Bodies. These Lewy Bodies contain the aggregated α-synuclein (α-syn) protein, which has been shown to be able to propagate from cell to cell and throughout different regions in the brain. Due to its central role in the pathology and the lack of a curative treatment for PD, an increasing number of studies have aimed at targeting this protein for therapeutics. Here, we reviewed and discussed the many different approaches that have been studied to inhibit α-syn accumulation via direct and indirect targeting. These analyses have led to the generation of multiple clinical trials that are either completed or currently active. These clinical trials and the current preclinical studies must still face obstacles ahead, but give hope of finding a therapy for PD with time.

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Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies

Cited by 102 publications

References 40 publications

MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy

MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

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