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

Grandjean, Jean-Marc; Jiu, Alexander Y; West, John W; Aoyagi, Atsushi; Droege, Daniel G; Elepano, Manuel; Hirasawa, Makoto; Hirouchi, Masakazu; Murakami, Ryo; Lee, Joanne; Sasaki, Koji; Hirano, Shimpei; Ohyama, Takao; Tang, Benjamin C.; Vaz, Roy J.; Inoue, Masahiro; Olson, Steven H.; Prusiner, Stanley B.; Conrad, Jay C.; Paras, Nick A.

doi:10.1021/acsmedchemlett.9b00480

Cited by 11 publications

(13 citation statements)

References 16 publications

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“…We constructed the three-channel training dataset to model infectious tau propagation similar to the archival HCS dataset (Methods). HEK293T cells were transfected to overexpress a YFP-tau mutant containing a familial mutation (P301S) which increases the propensity of tau to form prions that aggregate 25,37 . We then seeded the cells with an infectious mouse brain lysate passaged once through HEK293T cells expressing the microtubule-binding repeat domain of human tau with the P301L and V337M mutations.…”

Section: We Constructed a Drug Screen Dataset Of Tau Prion Propagatio...mentioning

confidence: 99%

Trans-channel fluorescence learning improves high-content screening for Alzheimer’s disease therapeutics

et al. 2022

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In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations may hinder the use of certain fluorescent markers. Here, we present a deep learning method for overcoming this limitation. We accurately generated predicted fluorescent signals from other related markers and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of biologically active compounds for Alzheimer's disease (AD) from high-content high-throughput screening (HCS). The ML method identified novel compounds that effectively blocked tau aggregation, which would have been missed by traditional screening approaches unguided by ML. The method improved triaging efficiency of compound rankings over conventional rankings by raw image channels. We reproduced this ML pipeline on a biologically independent cancer-based dataset, demonstrating its generalizability.The approach is disease-agnostic and applicable across diverse fluorescence microscopy datasets..

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Section: We Constructed a Drug Screen Dataset Of Tau Prion Propagatio...mentioning

confidence: 99%

Trans-channel fluorescence learning improves high-content screening for Alzheimer’s disease therapeutics

et al. 2022

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“…Pooled brain homogenate from 6−7 month old Tg2541 mice (both male and female) was prepared as previously described 25 . Briefly, a 10% (weight/volume) homogenate in DPBS was prepared using a rotor-stator type tissue homogenizer (Omni International).…”

Section: Phosphotungstic Acid Precipitation Of Tau Protein In Tg2541 Mouse Brain Samplesmentioning

confidence: 99%

“…HEK293T cells that overexpress the microtubule-binding repeat domain (RD) of 4R human tau with the P301L and V337M mutations 13 [TauRD(P301L/V337M)-YFP cells] were maintained in DMEM supplemented with 10% FBS and 1% penicillin/streptomycin. Tau seeds were prepared by passaging PTA-precipitated tau protein from Tg2541 mouse brain samples once through TauRD(P301L/V337M)-YFP cells and then collecting the cell lysate, as described previously 25 . All cells were cultured at 37°C and 5% CO 2 in a humidified incubator until analysis.…”

Section: Experimental Setup For the Cellular Tau(p301s)-yfp Aggregation Assay Training Datasetmentioning

confidence: 99%

Trans-channel fluorescence learning improves high-content screening for Alzheimer’s disease therapeutics

Wong

Conrad

Johnson

et al. 2021

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In microscopy-based drug screens, fluorescent markers carry critical information on how compounds affect different biological processes. However, practical considerations may hinder the use of certain fluorescent markers. Here, we present a deep learning method for overcoming this limitation. We accurately generated predicted fluorescent signals from other related markers, and validated this new machine learning (ML) method on two biologically distinct datasets. We used the ML method to improve the selection of potentially efficacious therapeutic compounds for Alzheimer’s disease (AD) from high-content high-throughput screening (HCS). The ML method identified novel compounds that effectively blocked tau aggregation, which would have been missed by traditional screening approaches unguided by ML. The ML method also improved triaging efficiency of compound rankings over a current in-house screening approach. We reproduced this ML method on a biologically independent cancer-based dataset, demonstrating its generalizability. The approach is disease-agnostic, and applicable across fluorescence microscopy datasets.

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“…Isoquinoline, a privileged heterocyclic core, constitutes a significant scaffold in several natural products and has numerous biological activities. 19 Despite being such a medical boon, very few synthetic modulations have been achieved on isoquinolines, possibly because of the long and tedious synthesis of isoquinoline cores. Isoquinoline derivatives carrying an aminocarbonyl group at the C-4 position are reported as potent cannabinoid receptor modulators 1a−c (Figure 1).…”

Section: ■ Introductionmentioning

confidence: 99%

Palladium-Catalyzed Aminocarbonylation of Isoquinolines Utilizing Chloroform-COware Chemistry

et al. 2022

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The carbonyl group forms an integral part of several drug molecules and materials; hence, synthesis of carbonylated compounds remains an intriguing area of research for synthetic and medicinal chemists. Handling toxic CO gas has several limitations; thus, using safe and effective techniques for in or ex situ generation of carbon monoxide from nontoxic and cheap precursors is highly desirable. Among several precursors that have been explored for the generation of CO gas, chloroform can prove to be a promising CO surrogate due to its cost-effectiveness and ready availability. However, the one-pot chloroform-based carbonylation reaction requires strong basic conditions for hydrolysis of chloroform that may affect functional group tolerability of substrates and scale-up reactions. These limitations can be overcome by a two-chamber reactor (COware) that can be utilized for ex situ CO generation through hydrolysis of chloroform in one chamber and facilitating safe carbonylation reactions in another chamber under mild conditions. The versatility of this “Chloroform-COware” technique is explored through palladium-catalyzed aminocarbonylation of medicinally relevant heterocyclic cores, viz., isoquinoline and quinoline.

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

Cited by 11 publications

References 16 publications

Trans-channel fluorescence learning improves high-content screening for Alzheimer’s disease therapeutics

Trans-channel fluorescence learning improves high-content screening for Alzheimer’s disease therapeutics

Trans-channel fluorescence learning improves high-content screening for Alzheimer’s disease therapeutics

Palladium-Catalyzed Aminocarbonylation of Isoquinolines Utilizing Chloroform-COware Chemistry

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