Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study

Jha, Vibhu; Galati, Salvatore; Volpi, Valerio; Ciccone, Lidia; Minutolo, Filippo; Rizzolio, Flavio; Granchi, Carlotta; Poli, Giulio; Tuccinardi, Tiziano

doi:10.1080/07391102.2020.1773314

Cited by 5 publications

(4 citation statements)

References 39 publications

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“…The compound disrupts citrate binding and recognition by inducing conformational changes in the citrate domain. This allosteric inhibition underscores the potential of the allosteric site as a promising target in drug discovery, enhancing the likelihood of ACLY inhibitors (Jha et al, 2021;K. Liang & Dai, 2022;P.…”

Section: Ndi-091143mentioning

confidence: 83%

ATP-Citrate Lyase (ACLY): An Extensive Investigation from Molecular Insight to Therapeutic implications

Biju,

Chennam Lakshmikumar,

Rengasamy

2024

NRFHH

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ATP Citrate Lyase (ACLY) is a central enzyme bridging carbohydrate metabolism and lipid biosynthesis, crucial for various physiological processes and implicated in numerous pathologies. This review comprehensively describes ACLY, a pivotal enzyme at lipid biosynthesis and cellular metabolism interface. It serves as crucial role for several physiological functions, making it a highly valued topic for research. Starting with a description of the biochemistry and molecular biology of ACLY, elucidating its structural features, functions, and regulatory mechanisms, particularly in lipid synthesis and histone acetylation. Considering the pathophysiological aspect, the review also examines the relationship between ACLY dysregulation and associated diseases, explaining its contribution to pathological conditions mechanistically. An explanation of ACLY inhibitors is as follows: an overview of these inhibitors, an understanding of their mechanisms of action, and an analysis of their effectiveness and specificity. The following sections transition from preclinical studies, summarising key findings and knowledge into therapeutic potential, to clinical trials. The review offers updated information about ACLY research, integrating data from multiple sources to give an in-depth understanding. It concludes with the challenges and outlook facing the developing ACLY inhibitors, considering the strategies to overcome these challenges and the upcoming path in research and development in this promising field. This comprehensive examination not only encapsulates the knowledge at present but also aims to inspire and guide future inquiries into the complex realm of ACLY and its potential as a therapeutic target, ultimately improving patient outcomes and quality of life.

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Section: Ndi-091143mentioning

confidence: 83%

ATP-Citrate Lyase (ACLY): An Extensive Investigation from Molecular Insight to Therapeutic implications

Biju,

Chennam Lakshmikumar,

Rengasamy

2024

NRFHH

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“…В случае успеха БК группа ингибиторов АЦЛ, вероятно, пополнится новыми представителями, о чем говорят результаты фармакофорного скрининга [39].…”

Section: The Effects Of Bempedoic Acid эффекты бемпедоевой кислотыunclassified

The Pathogenetic Basis of the Action of Bempedoic Acid

Petrosyan

Rud

Polyakov

et al. 2023

Racionalʹnaâ farmakoterapiâ v kardiologii

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The modern cardiology has a wide range of medications which affect various pathogenetic links of atherosclerosis, but even the best of them still obtain disadvantages causing intolerance and medicine discontinuation. The development of new hypolipidemic medications will allow not only to introduce alternative therapies into the cardiology practice, but also to completely execute the strategy of residual risk reduction by utilizing rational combinations of medications. One of such alternatives could be bempedoic acid, which can have a positive effect on a number of endpoints as the results of third phase trials have shown. These effects are also confirmed in Mendelian randomization studies. The mechanism of action of bempedoic acid is presumably associated with inhibition of the activity of ATP citrate lyase – the enzyme responsible for the breakdown of citrate into acetyl-CoA and oxaloacetate. Acetyl-CoA, in turn, is used by the cell to synthesize cholesterol and fatty acids. Thus, bempedoic acid affects in the same metabolic pathway as statins, but at an earlier stage. According to this, it is possible that medications of these classes will have similar side effects and pleiotropic effects associated with modulation of the mevalonic pathway, such as prenylation regulatory proteins (small GTPases) or reduction of coenzyme Q synthesis. However, there are also some specific features of the pharmacodynamics and pharmacokinetics of bempedoic acid to be considered. In particular, once entered the body, it must be activated via esterification by very long-chain acyl-CoA synthetase-1. The enzyme isoform required for this process is expressed in a tissue-specific manner and, for example, is absent in skeletal myocytes. In addition, citrate, oxaloacetate, and acetyl-CoA are important regulators of many intracellular processes: metabolism, growth and proliferation, mechanotransduction, posttranslational modifications of histones and other proteins. The levels of all three substances are altered by bempedoic acid, although no firm conclusions about the effects of these changes can be drawn at this time. The mentioned features probably have a significant impact on the clinical profile of bempedoic acid and underlie the differences from statins already observed in third phase trials, including, for example, a reduced risk of the onset or worsening of diabetes mellitus while taking bempedoic acid.

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“…It is a vital source of energy for the growth and metabolism of cancer cells. The ACLY-mediated conversion of citrate to acetyl-CoA is the basis for fatty acid synthesis ( 113 ). The protein released by HP results in the up-regulation of ACLY gene expression, promotes the synthesis of acetyl-CoA, and enhances the interaction between H. pylori (HP) and gastric epithelial cells, eventually leading to gastritis and epithelial damage ( 114 ).…”

Section: The Function Of Lipid Metabolism Related Enzymesmentioning

confidence: 99%

The Role of Lipid Metabolism in Gastric Cancer

Cui

Zhu

et al. 2022

Front. Oncol.

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Gastric cancer has been one of the most common cancers worldwide with extensive metastasis and high mortality. Chemotherapy has been found as a main treatment for metastatic gastric cancer, whereas drug resistance limits the effectiveness of chemotherapy and leads to treatment failure. Chemotherapy resistance in gastric cancer has a complex and multifactorial mechanism, among which lipid metabolism plays a vital role. Increased synthesis of new lipids or uptake of exogenous lipids can facilitate the rapid growth of cancer cells and tumor formation. Lipids form the structural basis of biofilms while serving as signal molecules and energy sources. It is noteworthy that lipid metabolism is capable of inducing drug resistance in gastric cancer cells by reshaping the tumor micro-environment. In this study, new mechanisms of lipid metabolism in gastric cancer and the metabolic pathways correlated with chemotherapy resistance are reviewed. In particular, we discuss the effects of lipid metabolism on autophagy, biomarkers treatment and drug resistance in gastric cancer from the perspective of lipid metabolism. In brief, new insights can be gained into the development of promising therapies through an in-depth investigation of the mechanism of lipid metabolism reprogramming and resensitization to chemotherapy in gastric cancer cells, and scientific treatment can be provided by applying lipid-key enzyme inhibitors as cancer chemical sensitizers in clinical settings.

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Discovery of a new ATP-citrate lyase (ACLY) inhibitor identified by a pharmacophore-based virtual screening study

Cited by 5 publications

References 39 publications

ATP-Citrate Lyase (ACLY): An Extensive Investigation from Molecular Insight to Therapeutic implications

ATP-Citrate Lyase (ACLY): An Extensive Investigation from Molecular Insight to Therapeutic implications

The Pathogenetic Basis of the Action of Bempedoic Acid

The Role of Lipid Metabolism in Gastric Cancer

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