4 results on '"Bate JR"'
Search Results
2. Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.
- Author
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Van de Poël A, Toledo-Sherman L, Breccia P, Cachope R, Bate JR, Angulo-Herrera I, Wishart G, Matthews KL, Martin SL, Peacock M, Barnard A, Cox HC, Jones G, McAllister G, Vater H, Esmieu W, Clissold C, Lamers M, Leonard P, Jarvis RE, Blackaby W, Eznarriaga M, Lazari O, Yates D, Rose M, Jang SW, Muñoz-Sanjuan I, and Dominguez C
- Subjects
- Animals, Ataxia Telangiectasia Mutated Proteins metabolism, Binding Sites, Brain metabolism, Class III Phosphatidylinositol 3-Kinases antagonists & inhibitors, Class III Phosphatidylinositol 3-Kinases metabolism, Crystallography, X-Ray, Drug Design, Half-Life, Humans, Huntington Disease drug therapy, Male, Mice, Mice, Inbred C57BL, Molecular Dynamics Simulation, Morpholinos chemistry, Pyridones metabolism, Pyridones therapeutic use, Pyrimidinones metabolism, Pyrimidinones therapeutic use, Structure-Activity Relationship, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Pyridones chemistry, Pyrimidinones chemistry
- Abstract
Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4 ) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.
- Published
- 2021
- Full Text
- View/download PDF
3. Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.
- Author
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Toledo-Sherman L, Breccia P, Cachope R, Bate JR, Angulo-Herrera I, Wishart G, Matthews KL, Martin SL, Cox HC, McAllister G, Penrose SD, Vater H, Esmieu W, Van de Poël A, Van de Bospoort R, Strijbosch A, Lamers M, Leonard P, Jarvis RE, Blackaby W, Barnes K, Eznarriaga M, Dowler S, Smith GD, Fischer DF, Lazari O, Yates D, Rose M, Jang SW, Muñoz-Sanjuan I, and Dominguez C
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Animals, Disease Models, Animal, Dogs, Humans, Madin Darby Canine Kidney Cells, Mice, Neuroprotective Agents metabolism, Neuroprotective Agents pharmacokinetics, Proof of Concept Study, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Huntington Disease drug therapy, Neuroprotective Agents therapeutic use
- Abstract
Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.
- Published
- 2019
- Full Text
- View/download PDF
4. Glycine induces a novel form of long-term potentiation in the superficial layers of the superior colliculus.
- Author
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Platt B, Bate JR, von Linstow Roloff E, and Withington DJ
- Subjects
- Animals, Calcium Channels metabolism, Carbonates metabolism, Chlorides metabolism, Dose-Response Relationship, Drug, GABA Antagonists pharmacology, Glycine Agents pharmacology, Guinea Pigs, In Vitro Techniques, Membrane Potentials drug effects, Picrotoxin pharmacology, Receptors, Glycine metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Strychnine pharmacology, Superior Colliculi metabolism, Glycine pharmacology, Long-Term Potentiation drug effects, Superior Colliculi drug effects
- Abstract
1. The mammalian superior colliculus (SC) is a midbrain nucleus containing space maps of different sensory modalities which show various forms of age- and activity-dependent plasticity in vivo and in vitro. In the present study, we aimed to characterize the role of glycine (Gly) receptors in the SC, and we observed that application of glycine (Gly; 500 microM and 3 mM) for 7 min to SC slices of adult guinea-pigs caused a novel form of long-term potentiation (termed LTPgly) of evoked excitatory postsynaptic potentials recorded in the superficial layers. 2. The strength of potentiation was found to be concentration-dependent and partially independent from synaptic stimulation. 3. LTPgly did not involve NMDA receptor activation as proven by the lack of inhibition by 100 microM D,L-2-amino-5-phosphonovaleric acid (APV) and 10 microM MK-801. 4. LTPgly could only be masked but not prevented by strychnine (100 microM) and remained undisturbed in the presence of picrotoxin (100 microM). 5. Inhibition of carbonic anhydrase by acetazolamide (20 microM) had no effect on LTPgly suggesting that the excitatory action of Gly is not due to a differential breakdown of the Cl-/HCO3 gradients. 6. As indicated by the inhibition of LTPgly of the fEPSP slope by the L-type calcium channel blocker nifedipine (20 microM), voltage-dependent calcium channels are the source for Ca2+ elevation as the intracellular trigger. 7. Our data provide the first evidence for a role of Gly in SC synaptic transmission. They illustrate a so far unknown action of Gly which can lead to long-lasting changes of synaptic efficacy and which is not mediated via NMDA-related or strychnine-sensitive binding sites.
- Published
- 1998
- Full Text
- View/download PDF
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