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Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity.

ABSTRACT: Tau prions feature in the brains of patients suffering from Alzheimer's disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified as a hit with an EC₅₀ value of 390 nM and 0.04 K _p,uu. Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC₅₀ = 15 nM; K _p,uu = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.

SUBMITTER: Grandjean JM

PROVIDER: S-EPMC7025388 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity.

Grandjean Jean-Marc M JM Jiu Alexander Y AY West John W JW Aoyagi Atsushi A Droege Daniel G DG Elepano Manuel M Hirasawa Makoto M Hirouchi Masakazu M Murakami Ryo R Lee Joanne J Sasaki Koji K Hirano Shimpei S Ohyama Takao T Tang Benjamin C BC Vaz Roy J RJ Inoue Masahiro M Olson Steven H SH Prusiner Stanley B SB Conrad Jay J Paras Nick A NA

ACS medicinal chemistry letters 20200130 2

Tau prions feature in the brains of patients suffering from Alzheimer's disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified as a hit with an EC50 value of 390 nM and 0.04 K p,uu. Analogs were synthesized using a hy ...[more]

PMID: 32071678

Dataset Information

Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity.

Publications

Discovery of 4-Piperazine Isoquinoline Derivatives as Potent and Brain-Permeable Tau Prion Inhibitors with CDK8 Activity.

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