دورية أكاديمية
أعرض في EDS

Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors.

التفاصيل البيبلوغرافية
العنوان: Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors.
المؤلفون: Matheson CJ; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA., Casalvieri KA; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA., Backos DS; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA., Minhajuddin M; Division of Hematology, University of Colorado Anschutz Medical Campus, 12700 E 19th Avenue, Aurora, CO, 80045, USA., Jordan CT; Division of Hematology, University of Colorado Anschutz Medical Campus, 12700 E 19th Avenue, Aurora, CO, 80045, USA., Reigan P; Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA. Electronic address: philip.reigan@cuanschutz.edu.
المصدر: European journal of medicinal chemistry [Eur J Med Chem] 2020 Jul 01; Vol. 197, pp. 112316. Date of Electronic Publication: 2020 Apr 16.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Editions Scientifiques Elsevier Country of Publication: France NLM ID: 0420510 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1768-3254 (Electronic) Linking ISSN: 02235234 NLM ISO Abbreviation: Eur J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
مواضيع طبية MeSH: AMP-Activated Protein Kinases/*metabolism , Antineoplastic Agents/*pharmacology , Oxindoles/*pharmacology , Protein Kinase Inhibitors/*pharmacology, AMP-Activated Protein Kinases/chemistry ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/metabolism ; Cell Survival/drug effects ; Drug Screening Assays, Antitumor ; Humans ; K562 Cells ; Molecular Docking Simulation ; Oxindoles/chemical synthesis ; Oxindoles/metabolism ; Protein Binding ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/metabolism
مستخلص: AMP-activated protein kinase (AMPK) is a central metabolic regulator that promotes cancer growth and survival under hypoxia and plays a role in the maintenance of cancer stem cells. A major challenge to interrogating the potential of targeting AMPK in cancer is the lack of potent and selective small molecule inhibitors. Compound C has been widely used as an AMPK inhibitor, but it lacks potency and has a poor selectivity profile. The multi-kinase inhibitor, sunitinib, has demonstrated potent nanomolar inhibition of AMPK activity and has scope for modification. Here, we have designed and synthesized several series of oxindoles to determine the structural requirements for AMPK inhibition and to improve selectivity. We identified two potent, novel oxindole-based AMPK inhibitors that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common recptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. Our studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential.
Competing Interests: Declaration of competing interest The authors disclose no potential conflicts of interest.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
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معلومات مُعتمدة: R01 CA200707 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: AMPK; Cancer; Inhibitor; Kinase; Metabolism; Structure-activity relationship
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Oxindoles)
0 (Protein Kinase Inhibitors)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
تواريخ الأحداث: Date Created: 20200426 Date Completed: 20201027 Latest Revision: 20231111
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7409528
DOI: 10.1016/j.ejmech.2020.112316
PMID: 32334266
قاعدة البيانات: MEDLINE
الوصف
تدمد:1768-3254
DOI:10.1016/j.ejmech.2020.112316