Discovery of novel glycogen synthase kinase-3α inhibitors: Structure-based virtual screening, preliminary SAR and biological evaluation for treatment of acute myeloid leukemia

Wang, Yanxing; Dou, Xiaodong; Jiang, Lan; Jin, Hongwei; Zhang, Lihe; Zhang, Liangren; Liu, Zhenming

doi:10.1016/j.ejmech.2019.03.039

Cited by 22 publications

(10 citation statements)

References 55 publications

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“…Therefore, the majority of inhibitors which have been synthesized compete with the ATP-binding site of GSK-3 paralogs with low selectivity. Nevertheless, isoform-selective inhibitors have been disclosed, including BRD0705, compound 27, and compound 28_14 (which target GSK-3α [ 82 , 191 , 192 ]) or TWS199 (which targets GSK-3β [ 193 ]). Both BRD0705 and compound 28 - 14 have been tested in preclinical models of acute myelogenous leukemia (AML) with promising results [ 194 ].…”

Section: New Strategies For Targeting Gsk-3 In Cancer Cellsmentioning

confidence: 99%

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Martelli

Paganelli

Evangelisti

et al. 2022

Cells

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Glycogen synthase kinase-3 (GSK-3) is an evolutionarily conserved, ubiquitously expressed, multifunctional serine/threonine protein kinase involved in the regulation of a variety of physiological processes. GSK-3 comprises two isoforms (α and β) which were originally discovered in 1980 as enzymes involved in glucose metabolism via inhibitory phosphorylation of glycogen synthase. Differently from other proteins kinases, GSK-3 isoforms are constitutively active in resting cells, and their modulation mainly involves inhibition through upstream regulatory networks. In the early 1990s, GSK-3 isoforms were implicated as key players in cancer cell pathobiology. Active GSK-3 facilitates the destruction of multiple oncogenic proteins which include β-catenin and Master regulator of cell cycle entry and proliferative metabolism (c-Myc). Therefore, GSK-3 was initially considered to be a tumor suppressor. Consistently, GSK-3 is often inactivated in cancer cells through dysregulated upstream signaling pathways. However, over the past 10–15 years, a growing number of studies highlighted that in some cancer settings GSK-3 isoforms inhibit tumor suppressing pathways and therefore act as tumor promoters. In this article, we will discuss the multiple and often enigmatic roles played by GSK-3 isoforms in some chronic hematological malignancies (chronic myelogenous leukemia, chronic lymphocytic leukemia, multiple myeloma, and B-cell non-Hodgkin’s lymphomas) which are among the most common blood cancer cell types. We will also summarize possible novel strategies targeting GSK-3 for innovative therapies of these disorders.

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Section: New Strategies For Targeting Gsk-3 In Cancer Cellsmentioning

confidence: 99%

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Martelli

Paganelli

Evangelisti

et al. 2022

Cells

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“…The major Note, a reverse (non-conventional) sequential approach is also involved in vitro screening as part of the screening cascade. Wang et al [33] intended to identify potent glycogen synthase kinase 3alpha (GSK-3alpha) inhibitors. Based on the related isoenzymes first a homology model was generated then 300,000 compounds were docked.…”

Section: Integration Involving In Silico and In Vitro Screening Our Approachmentioning

confidence: 99%

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

Szilágyi¹,

Flachner²,

Hajdú³

et al. 2021

Molecules

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Rapid in silico selection of target focused libraries from commercial repositories is an attractive and cost-effective approach in early drug discovery. If structures of active compounds are available, rapid 2D similarity search can be performed on multimillion compounds’ databases. This approach can be combined with physico-chemical parameter and diversity filtering, bioisosteric replacements, and fragment-based approaches for performing a first round biological screening. Our objectives were to investigate the combination of 2D similarity search with various 3D ligand and structure-based methods for hit expansion and validation, in order to increase the hit rate and novelty. In the present account, six case studies are described and the efficiency of mixing is evaluated. While sequentially combined 2D/3D similarity approach increases the hit rate significantly, sequential combination of 2D similarity with pharmacophore model or 3D docking enriched the resulting focused library with novel chemotypes. Parallel integrated approaches allowed the comparison of the various 2D and 3D methods and revealed that 2D similarity-based and 3D ligand and structure-based techniques are often complementary, and their combinations represent a powerful synergy. Finally, the lessons we learnt including the advantages and pitfalls of the described approaches are discussed.

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“…GSK-3β inhibitors with new scaffolds are needed. Computer-aided drug design has shown to be an effective approach to identify novel GSK-3 inhibitors [29]. Recently, various methods have been explored to improve the discriminatory ability of molecular docking [30][31][32].…”

Section: Identification Of Novel Gsk-3β Inhibitors Through Docking Based Virtual Screening and Biological Evaluationmentioning

confidence: 99%

Identification of Novel GSK-3β Inhibitors through Docking Based Virtual Screening and Biological Evaluation

Xu¹,

Sy²,

Yx³

et al. 2021

austinjcancerclinres

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GSK-3β is a key regulator in insulin, Wnt and NF-κB signaling pathways. Dysregulation of GSK-3β is often related to tumors and diabetes. Inhibiting it might provide cure for diabetes, tumors, neurodegeneration and brain ischemia. Although there are a number of reported GSK-3β inhibitors, the scaffold is limited. Herein we report a discriminatory analysis-based molecular docking on the Specs database, and identiﬁed 3 novel GSK-3β inhibitors with moderate IC50 (ranging from 17.42 μM to 6.74 μM) in the following in vitro biological test. Further dynamic simulations and docking pose analysis were performed to give a better understanding on the binding conformation of 3 hit compounds AK- 777/09836064, AK-968/37185006 and AN-698/41607072, which would provide basis for further optimization.

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Discovery of novel glycogen synthase kinase-3α inhibitors: Structure-based virtual screening, preliminary SAR and biological evaluation for treatment of acute myeloid leukemia

Cited by 22 publications

References 55 publications

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

Rapid Identification of Potential Drug Candidates from Multi-Million Compounds’ Repositories. Combination of 2D Similarity Search with 3D Ligand/Structure Based Methods and In Vitro Screening

Identification of Novel GSK-3β Inhibitors through Docking Based Virtual Screening and Biological Evaluation

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