The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases

Hu, Lufei; Boxer, Peter A.; Kesten, Suzanne R.; Lei, Huangshu; Wustrow, David; Moreland, D.W.; Zhang, Liming; Ahn, Kay; Ryder, Todd R.; Liu, Xiaohong; Rubin, John R.; Fahnoe, Kelly; Carroll, Richard T.; Dutta, Satavisha; Fahnoe, Douglass C.; Probert, Albert W.; Roof, Robin L.; Rafferty, Michael; Kostlan, Catherine R.; Scholten, Jeffrey D.; Hood, Molly M.; Ren, Xiao; Schielke, Gerald P.; Su, Ti‐Zhi; Taylor, Charles P.; Mistry, Anil; McConnell, Patrick I.; Hasemann, Charles A.; Ohren, Jeffrey F.

doi:10.1016/j.bmcl.2005.07.058

Cited by 25 publications

(24 citation statements)

References 9 publications

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“…This pocket is blocked by a methionine side chain (Met-241) in the protein crystal structure of 3 (in cyan, Figure 2a), however, rotation of the thioether side chain through 180°f acilitated binding of the larger substituent ( Figure 2). This movement had not previously been observed in any other BCATm protein structures identified in our screening 38 or described in the literature; 11,12 in the absence of this information, traditional fragment optimization techniques may not have identified this induced pocket from fragment hits 2 and 3.…”

Section: ■ Results and Discussionmentioning

confidence: 59%

“…The mixture was heated at reflux for 16 h. The mixture was cooled to room temperature, and a fine off-white solid was deposited, collected by filtration, washed with water, and dried in a vacuum oven to give the title product 9 as a off-white solid (91 mg, 67%). 1 (11). Ethyl 5-methyl-3-oxohexanoate (153 mg, 0.888 mmol) was added to a suspension of 5-amino-3-((4-chlorobenzyl)amino)-1H-pyrazole-4-carbonitrile 18a (200 mg, 0.807 mmol) in acetic acid (2 mL).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits

et al. 2015

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The hybridization of hits, identified by complementary fragment and high throughput screens, enabled the discovery of the first series of potent inhibitors of mitochondrial branched-chain aminotransferase (BCATm) based on a 2-benzylamino-pyrazolo[1,5-a]pyrimidinone-3-carbonitrile template. Structure-guided growth enabled rapid optimization of potency with maintenance of ligand efficiency, while the focus on physicochemical properties delivered compounds with excellent pharmacokinetic exposure that enabled a proof of concept experiment in mice. Oral administration of 2-((4-chloro-2,6-difluorobenzyl)amino)-7-oxo-5-propyl-4,7-dihydropyrazolo[1,5-a]pyrimidine-3-carbonitrile 61 significantly raised the circulating levels of the branched-chain amino acids leucine, isoleucine, and valine in this acute study.

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Section: ■ Results and Discussionmentioning

confidence: 59%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits

et al. 2015

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“…We infected IDH1/2 wild-type HOG human glioma cells (Reitman et al, 2011) with a lentivirus encoding the canonical R132H IDH1 mutant, wild-type IDH1, or with the empty vector (EV) (Figure 1B). We then did GC-MS-based metabolomic profiling of the resulting stable cell lines, as well as parental HOG cells that were treated with BCAT inhibitors (Compound 2 or gabapentin) (Hu et al, 2006) or were infected to produce one of two BCAT1 shRNAs or a control shRNA (Figures 1C and 1D). IDH1 R132H increased the abundance of the BCAAs and depleted glutamate and the BCKAs α-keto-β-methylvalerate (KMV) and α-ketoisocaproate (KIC), as did pharmacologically or genetically inhibiting BCAT1 (Figure 1D).…”

Section: Resultsmentioning

confidence: 99%

Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma

McBrayer

Mayers

DiNatale

et al. 2018

Cell

285

266

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IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.

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“…Inhibition of BCAT may be useful for the treatment of behavioral and neurodegenerative disorders (Hu et al, 2006). As the expression of BCAT2 was decreased after birth ( Figure 7G ), BCAT2 expression pattern may be different in neuron injury.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-182 Regulates Neurite Outgrowth Involving the PTEN/AKT Pathway

Wang

Lü

et al. 2017

Front. Cell. Neurosci.

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MicroRNAs are implicated in neuronal development and maturation. Neuronal maturation, including axon outgrowth and dendrite tree formation, is regulated by complex mechanisms and related to several neurodevelopmental disorders. We demonstrated that one neuron-enriched microRNA, microRNA-182 (miR-182), played a significant role in regulating neuronal axon outgrowth and dendrite tree formation. Overexpression of miR-182 promoted axon outgrowth and complexity of the dendrite tree while also increasing the expression of neurofilament-M and neurofilament-L, which provide structural support for neurite outgrowth. However, a reduction of miR-182 inhibited neurite outgrowth. Furthermore, we showed that miR-182 activated the AKT pathway by increasing AKT phosphorylation on S473 and T308 and inhibiting PTEN activity by increasing phosphorylation on S380. Inhibition of AKT activity with the PI3-K inhibitor LY294002 could downregulate AKT and PTEN phosphorylation and suppress axon outgrowth. In addition, we showed that BCAT2 might be the target of miR-182 that takes part in the regulation of neuronal maturation; blockage of endogenous BCAT2 promotes axon outgrowth and AKT activity. These observations indicate that miR-182 regulates axon outgrowth and dendrite maturation involving activation of the PTEN/AKT pathway.

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The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases

Cited by 25 publications

References 9 publications

The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits

The Discovery of in Vivo Active Mitochondrial Branched-Chain Aminotransferase (BCATm) Inhibitors by Hybridizing Fragment and HTS Hits

Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma

MicroRNA-182 Regulates Neurite Outgrowth Involving the PTEN/AKT Pathway

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