Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor

Zang, Yong-Jun; Tai, Luyang; Hu, Yuan-Yang; Wang, Yu; Sun, Hongbin; Wen, Xiaoan; Yuan, Haoliang; Dai, Liang

doi:10.1021/acs.jcim.2c00345

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…Using the MDH coupled enzyme assay, NDI-091143 was the most effective inhibitor of ACLY with an IC 50 of 44.0 ± 3.0 nM. Moreover, compound 2 demonstrated potent inhibitory activity against ACLY with an IC 50 value of 69.7 ± 9.6 nM, like the effectiveness of NDI-091143, the measured IC 50 values correlated with their anticipated binding free energy values, highlighting the importance of the "ring-closing" approach in achieving proficient ACLY inhibition (Zang et al, 2022).…”

Section: Ndi-091143mentioning

confidence: 82%

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: 82%

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

Biju,

Chennam Lakshmikumar,

Rengasamy

2024

NRFHH

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“…140 Compound 31 exhibited considerable inhibitory activity and target affinity and significantly enhanced human liver microsomal stability (t 1/2 = 531 min). 140 5.3.2.4. Bempedoic Acid and Derivatives.…”

Section: Citrate Analoguesmentioning

confidence: 99%

“…Based on the folded conformation of NDI-091143, a macrocyclic strategy has been employed to discover compound 31 (Figure B) . Compound 31 exhibited considerable inhibitory activity and target affinity and significantly enhanced human liver microsomal stability ( t 1/2 = 531 min) …”

Section: Modulators Targeting Citrate Transport and Metabolismmentioning

confidence: 99%

Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery

Zhang

Qiu

et al. 2023

J. Med. Chem.

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Lipid metabolism disorder is closely related to metabolic diseases, inflammation, and cancer. The concentration of citrate in the cytosol has a significant impact on lipid synthesis. The expression of citrate transporters (SLC13A5 and SLC25A1) and metabolic enzymes (ACLY) proves to be substantially raised in various diseases related to disorders of lipid metabolism, such as hyperlipemia, nonalcoholic fatty liver disease, and prostate cancer. Targeting key proteins in the citrate transport and metabolic pathways is considered an effective strategy for treating various metabolic diseases. However, there is currently only one ACLY inhibitor approved for marketing, and no SLC13A5 inhibitor has entered clinical research. Further development of drugs targeting citrate transport and metabolism is needed for the treatment of metabolic diseases. This perspective summarizes the biological role, therapeutic potential, and research progress of citrate transport and metabolism and then discusses the achievements and prospects of modulators targeting citrate transport and metabolism for therapeutic applications.

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“…Its synthesis contains a ring-closing C-N bond formation reaction. 199 Fibroblast growth factor receptors (FGFRs) have a bold pattern in numerous cancers. Currently, the effectiveness of selective FGFRs-inhibitors is being evaluated in clinical trials as potential ant-cancer agents.…”

Section: Bio-active Compounds Containing Other N-heterocyclicmentioning

confidence: 99%

Applications of palladium-catalyzed C–N cross-coupling reactions in pharmaceutical compounds

et al. 2023

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Discovery of a Novel Macrocyclic ATP Citrate Lyase Inhibitor

Cited by 6 publications

References 31 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

Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery

Applications of palladium-catalyzed C–N cross-coupling reactions in pharmaceutical compounds

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