Discovery of new LXRβ agonists as glioblastoma inhibitors

Chen, Hao; Chen, Ziyang; Zhang, Zizhen; Li, Yali; Zhang, Shu-Shu; Jiang, Fuqiang; Wei, Junkang; Ding, Peng; Zhou, Huihao; Gu, Qiong; Xu, Jing

doi:10.1016/j.ejmech.2020.112240

Cited by 16 publications

(17 citation statements)

References 42 publications

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“…To overcome the selectivity, Chen et al screened 9500 in-house libraries using machine-learning-based virtual screening, which resulted in 59 biologically relevant compounds with 13 LXRβ agonists. 137 Further optimization efforts led to the identification of the selective LXRβ agonist 285, which selectively binds to LXRβ (IC 50 = 86 μM) and inhibits the growth of the U-87EGFRvIII cell line, with IC 50 = 1.78 μM. Moreover, 285 displayed significant anti-tumor activity over the in vivo xenograft model and showed promising PK properties ( Figure 62 E).…”

Section: Recent Medicinal Chemistry Campaignsmentioning

confidence: 99%

“…The selectivity is only accomplished by targeting Val versus Ile, the only variance in the binding pocket. To overcome the selectivity, Chen et al screened 9500 in-house libraries using machine-learning-based virtual screening, which resulted in 59 biologically relevant compounds with 13 LXRβ agonists . Further optimization efforts led to the identification of the selective LXRβ agonist 285, which selectively binds to LXRβ (IC 50 = 86 μM) and inhibits the growth of the U-87EGFRvIII cell line, with IC 50 = 1.78 μM.…”

Section: Recent Medicinal Chemistry Campaignsmentioning

confidence: 99%

“…Notably, at the preliminary and preclinical levels, medicinal chemists have explored synthetic adducts as well as natural product libraries to furnish new chemical architectures for the treatment of GBM. − Imaging tools and chemical probes for GBM (radio-iodinated tracers with specificity to PARP-1, microtubules, 18 F-labeled radiotracers, carborane-containing boron dipyrromethenes, , and cyanine–gemcitabine) have also been generated. Moreover, many preliminary studies merely focusing on the cellular effects of the new scaffolds have also been included in this work. − Although mechanistic studies were not performed, the study results appear to be promising, and the pinpointed potent scaffolds can be subjects of future investigation. Importantly, the literature covered in this Perspective validates the potential of numerous enzymes/proteins/receptors as therapeutic targets in GBM.…”

Section: Introductionmentioning

confidence: 99%

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Glioblastoma: Current Status, Emerging Targets, and Recent Advances

et al. 2022

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Glioblastoma (GBM) is a highly malignant brain tumor characterized by a heterogeneous population of genetically unstable and highly infiltrative cells that are resistant to chemotherapy. Although substantial efforts have been invested in the field of anti-GBM drug discovery in the past decade, success has primarily been confined to the preclinical level, and clinical studies have often been hampered due to efficacy-, selectivity-, or physicochemical property-related issues. Thus, expansion of the list of molecular targets coupled with a pragmatic design of new small-molecule inhibitors with central nervous system (CNS)-penetrating ability is required to steer the wheels of anti-GBM drug discovery endeavors. This Perspective presents various aspects of drug discovery (challenges in GBM drug discovery and delivery, therapeutic targets, and agents under clinical investigation). The comprehensively covered sections include the recent medicinal chemistry campaigns embarked upon to validate the potential of numerous enzymes/proteins/receptors as therapeutic targets in GBM.

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Section: Recent Medicinal Chemistry Campaignsmentioning

confidence: 99%

Section: Recent Medicinal Chemistry Campaignsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glioblastoma: Current Status, Emerging Targets, and Recent Advances

et al. 2022

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“…The Gilde scores were obtained by Schrödinger program. [35,36] Bioassay of Improving Behavioral Disorder in AlCl 3 Induced Dementia…”

Section: Molecular Dockingmentioning

confidence: 99%

Essential Oils from Spices Inhibit Cholinesterase Activity and Improve Behavioral Disorder in AlCl₃Induced Dementia

Chen

Xiang

Han

et al. 2021

Chemistry & Biodiversity

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The chemical compositions of essential oils (EOs) prepared from six spices including cinnamon, amomum tsao-ko, cardamom, amomum, black pepper and white pepper were analyzed by gas chromatography-mass spectrometry (GC/MS), which led to identify almost 200 volatile compounds. All EOs of spices showed cholinesterase inhibitory activity. Among them, pepper EO showed most potent acetylcholinesterase (AChE) inhibitory activity with IC 50 values of 8.54 μg/mL (black pepper EO) and 5.02 μg/mL (white pepper EO). Molecular docking and in vitro validation suggested that 3-carene, α-pinene and β-pinene with IC 50 value of 1.73, 2.66, and 14.75 μg/mL, respectively, might be active constituents of spices oil in inhibiting AChE. Furthermore, amomum tsao-ko EO and amomum EO can improve behavioral disorder in dementia zebrafish induced by aluminum trichloride (AlCl 3 ).

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“…Glu 281 , whose energy was highest in both LXRβ-cpd.2 and LXRβ-cpd.8 system, showed an extraordinary ΔG polar of 2.48 kcal•mol -1 and 8.80 kcal•mol -1 , respectively. Glu 281 was considered as a hydrophilic site which is able to bind to ligand in the form of hydrogen bonds[77]. Hydrogen bonds are usually considered as a set of dispersion force and intermolecular or interatomic electrostatic interaction[78], whose energy is represented by ΔG MM .…”

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confidence: 99%

Identifying selective agonists targeting LXRβ from terpene compounds of alismatis rhizoma

Lin

et al. 2021

J Mol Model

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Hyperlipidemia is thought as an important contributor to coronary disease, diabetes and fatty liver. Liver X receptors β (LXRβ) was considered as a validated target for hyperlipidemia therapy due to its role in regulating cholesterol homeostasis and immunity. However, many current drugs applied in clinic are not selectively targeting LXRβ and they can also activate LXRα which activate SREBP-1c worked as activator of lipogenic genes. Therefore, exploiting agonists selectively targeting LXRβ are urgent. Here, computational tools were used to screen potential agonists selectively targeting LXRβ from 112 terpenes of Alismatis Rhizoma. Firstly, structural analysis between selective and nonselective agonists were used to explore key residues of selective binding with LXRβ. Our data indicated that Phe 271 , Ser 278 , Met 312 , His 435 , Trp 457 were important to compounds binding with LXRβ, suggesting that engaging ligand interaction with these residues may provide directions for development of ligands with improved selective pro les. Then, ADMET analysis, molecular docking, MD simulations and calculation of binding free energy and its decomposition were executed to screen the agonists whose bioactivity were favorable from 112 terpenes of Alismatis Rhizoma. We found that two triterpenes 16-hydroxy-alisol B 23-acetate and Alisol M 23-acetate showed favorable ADMET properties and high binding a nity against LXRβ. These compounds could be considered as promising selective agonists targeting LXRβ. Our work provides an alternative strategy for screening agonists selectively targeting LXRβ from Alismatis Rhizoma for hyperlipidemia disease treatment.

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Discovery of new LXRβ agonists as glioblastoma inhibitors

Cited by 16 publications

References 42 publications

Glioblastoma: Current Status, Emerging Targets, and Recent Advances

Glioblastoma: Current Status, Emerging Targets, and Recent Advances

Essential Oils from Spices Inhibit Cholinesterase Activity and Improve Behavioral Disorder in AlCl₃Induced Dementia

Identifying selective agonists targeting LXRβ from terpene compounds of alismatis rhizoma

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Discovery of new LXRβ agonists as glioblastoma inhibitors

Cited by 16 publications

References 42 publications

Glioblastoma: Current Status, Emerging Targets, and Recent Advances

Glioblastoma: Current Status, Emerging Targets, and Recent Advances

Essential Oils from Spices Inhibit Cholinesterase Activity and Improve Behavioral Disorder in AlCl3Induced Dementia

Identifying selective agonists targeting LXRβ from terpene compounds of alismatis rhizoma

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Essential Oils from Spices Inhibit Cholinesterase Activity and Improve Behavioral Disorder in AlCl₃Induced Dementia