Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects

Wagner, Florence F.; Bishop, Joshua; Gale, Jennifer; Shi, Xi; Walk, Michelle; Ketterman, Joshua; Patnaik, Debasis; Barker, Doug; Walpita, Deepika; Campbell, Arthur J.; Nguyen, Shannon; Lewis, Michael C.; Ross, Linda S.; Weïwer, Michel; An, Wenlin; Germain, Andrew; Nag, Partha P.; Metkar, Shailesh; Kaya, Taner; Dandapani, Sivaraman; Olson, David E.; Barbe, Anne-Laure; Lazzaro, Fanny; Sacher, Joshua R.; Cheah, Jaime H.; Fei, David; Perez, José R.; Muñoz, Benito; Palmer, Michelle; Stegmaier, Kimberly; Schreiber, Stuart L.; Scolnick, Edward M.; Zhang, Yanling; Haggarty, Stephen J.; Holson, Edward B.; Pan, Jen Q.

doi:10.1021/acschembio.6b00306

Cited by 54 publications

(58 citation statements)

References 63 publications

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“…Although the final objective of generating more mDA cells was accomplished, improving mDA subtype specificity may require using improved GSK3i or activating Wnt/β‐catenin signalling with WNTs or mimetics. Recently, two new GSK3i with higher specificity have been described, BRD1652 and BRD0209 (Wagner et al, ). These two inhibitors have IC 50 values similar to that of CHIR99021, but their effects were more selective, with the closest off‐target inhibition (CDK3) requiring a 40 times higher concentration.…”

Section: Pharmacological Tools To Activate Wnt Signallingmentioning

confidence: 99%

Translation of WNT developmental programs into stem cell replacement strategies for the treatment of Parkinson's disease

Toledo

Gyllborg

Arenas

2017

British J Pharmacology

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Wnt signalling is a highly conserved pathway across species that is critical for normal development and is deregulated in multiple disorders including cancer and neurodegenerative diseases. Wnt signalling is critically required for midbrain dopaminergic (mDA) neuron development and maintenance. Understanding the molecular processes controlled by Wnt signalling may thus hold the key to understand the physiopathology and to develop novel therapies aimed at preventing the loss of mDA neurons in Parkinson's disease (PD). Pharmacological tools to activate Wnt signalling have been used to translate in vivo developmental processes into protocols for the generation of bona fide mDA neurons from human pluripotent stem cells. Moreover, these protocols are currently being fine-tuned to generate mDA neurons for clinical trials in PD. At the same time, a vast amount of molecular details of Wnt signalling continues to emerge and remains to be implemented into new protocols. We hereby review novel pharmacological tools to activate Wnt signalling and how single-cell RNA-sequencing is contributing to unravel the complexity of this pathway in the developing human ventral midbrain, generating novel hypotheses and identifying new players and opportunities to further improve cell replacement therapy for PD.

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Section: Pharmacological Tools To Activate Wnt Signallingmentioning

confidence: 99%

Translation of WNT developmental programs into stem cell replacement strategies for the treatment of Parkinson's disease

Toledo

Gyllborg

Arenas

2017

British J Pharmacology

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“…In the present study, the S values for analogs 3 – 5 were all 25 μ m . The K m value is 13 μ m , which was also obtained from another study . Given these values, the Δ G value of each compound was calculated.…”

Section: Resultsmentioning

confidence: 99%

Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay

Hsu

Lee

et al. 2017

Chem Biol Drug Des

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GSK3β kinase is a noteworthy target for discovery of the drugs that will be used to treat several diseases. In the effort to identify a new inhibitor lead compound, we utilized thermodynamic integration (TI)-molecular dynamics (MD) simulation and kinase assay to investigate the bindings between GSK3β kinase and five compounds that were analogous to a known inhibitor with an available crystal structure. TI-MD simulations of the first two compounds (analogs 1 and 2) were used for calibration. The computed binding affinities of analogs 1 and 2 agreed well with the experimental results. The rest three compounds (analogs 3-5) were newly obtained from a database search, and their affinity data were newly measured in our labs. TI-MD simulations predicted the binding modes and the computed ΔΔG values have a reasonably good correlation with the experimental affinity data. These newly identified inhibitors appear to be new leads according to our survey of GSK3β inhibitors listed in recent review articles. The predicted binding modes of these compounds should aid in designing new derivatives of these compounds in the future.

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“…We previously showed that WNT3A or CHIR could both trigger NC development from hPSC, and demonstrated that this process depends on β-CATENIN for NC formation under our low-WNT anterior NC formation conditions (Leung et al, 2016). However, at the high dose of ~10μM a few other kinases may also be inhibited by CHIR (Wagner et al, 2016). Of these, Wagner et.…”

Section: Discussionmentioning

confidence: 99%

WNT/β-CATENIN modulates the axial identity of ES derived human neural crest

Gomez¹,

Prasad²,

Wong³

et al. 2019

Preprint

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8The WNT/β-CATENIN pathway is critical for neural crest (NC) formation. However, the effects of the 1 9 magnitude of the signal remains poorly defined. Here we evaluate the consequences of WNT 2 0 magnitude variation in a robust model of human NC formation. This model is based on human 2 1 embryonic stem cells induced by WNT signaling through the small molecule CHIR9902. In addition 2 2 to its known effect on NC formation, we find that the WNT signal modulates the anterior-posterior 2 3 axial identity of NCCs in a dose dependent manner, with low WNT leading to anterior OTX+, HOX-2 4 NC, and high WNT leading to posterior OTX-, HOX+ NC. Differentiation tests of posterior NC confirm 2 5 expected derivatives including posterior specific adrenal derivatives, and display partial capacity to 2 6 generate anterior ectomesenchymal derivatives. Furthermore, unlike anterior NC, posterior NC 2 7 transit through a TBXT+/SOX2+ neuromesodermal precursor-like intermediate. Finally, we analyze 2 8 the contributions of other signaling pathways in posterior NC formation, and suggest a critical role for 2 9 FGF in survival/proliferation, and a requirement of BMP for NC maturation. As expected RA and 3 0 FGF are able to modulate HOX expression in the posterior NC, but surprisingly, RA supplementation 3 1 prohibits anterior, but only reduces, posterior NC formation. This work reveals for the first time that 3 2 the amplitude of WNT signaling can modulate the axial identity of NC cells in humans. 3 3 3 4 KEY WORDS: neural crest, WNT dosage/magnitude, anterior-posterior axis, HOX genes, 3 5 human embryonic stem cells.

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Inhibitors of Glycogen Synthase Kinase 3 with Exquisite Kinome-Wide Selectivity and Their Functional Effects

Cited by 54 publications

References 63 publications

Translation of WNT developmental programs into stem cell replacement strategies for the treatment of Parkinson's disease

Translation of WNT developmental programs into stem cell replacement strategies for the treatment of Parkinson's disease

Investigation of the bindings of a class of inhibitors with GSK3β kinase using thermodynamic integration MD simulation and kinase assay

WNT/β-CATENIN modulates the axial identity of ES derived human neural crest

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