ABSTRACT
Sirtuins (SIRT1-7), a class of deacetylases, play major roles in DNA damage repair, aging, and metabolism in yeast and in mammals. SIRT7 is localized in the nucleolus. It regulates cellular processes, including genomic stability, rDNA transcription, and cell proliferation, and plays a role in tumorigenesis. SIRT7 deacetylates its substrates histone H3 (at lysine 18) and p53. p53, a tumor suppressor, induces apoptosis or cell cycle arrest and is stabilized by acetylation. p53 deacetylation at K382 by SIRT7 suppressed cancer cell growth by attenuating p53 activity. Therefore, identification of novel SIRT7 enzyme inhibitors is important. In this study, we found a novel inhibitor of SIRT7 (ID: 97491) that decreased SIRT7 activity in a dose-dependent manner. ID: 97491 induced expression of p53 and its acetylation by inhibited SIRT7. Moreover, ID: 97491 upregulated apoptotic effects through the caspase related proteins and inhibited cancer growth in vivo. The study results suggest that ID: 97491 can be a potential candidate to inhibit the deacetylase activity of SIRT7 and prevent tumor progression by increasing p53 stability through acetylation at K373/382.
Subject(s)
Antineoplastic Agents/pharmacology , Enzyme Inhibitors/pharmacology , Sirtuins/antagonists & inhibitors , Acetylation/drug effects , Animals , Cell Line, Tumor , Disease Progression , Drug Discovery , Female , HEK293 Cells , Humans , Mice , Mice, Nude , Sirtuins/metabolism , Tumor Suppressor Protein p53/metabolism , Uterine Neoplasms/drug therapy , Uterine Neoplasms/metabolism , Uterine Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
Sirtuins, a family of NAD+-dependent deacetylase enzymes, have been identified as mammalian homologs of yeast silent information regulator 2 (SIR2). Sirtuin 6 (SIRT6) plays important roles in cell homeostasis, DNA damage repair, cancer suppression, and aging. SIRT6 overexpression improves metabolic diseases, such as hypercholesterolemia, cholesterol-related disease, and type 2 diabetes via AMP-activated protein kinase (AMPK) activation. SIRT6 is abundant in the liver and is a crucial target for patients with liver steatosis. Compounds for drug repositioning were screened to identify potential SIRT6 activators, and fluvastatin, a synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase that reduces cholesterol synthesis, was identified to activate SIRT6. When HepG2 cells were treated with fluvastatin, the expression of SIRT6 and phosphorylation of sterol regulatory element-binding protein (SREBP)-1 and AMPKα, which is regulated by SIRT6, increased. In this study, we examined the mechanism underlying cholesterol regulation by fluvastatin via SREBP-1 and AMPKα pathway and suggested that fluvastatin is an SIRT6 activator that regulates cholesterol homeostasis and fatty liver disease.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Fluvastatin/pharmacology , Sirtuins/metabolism , Sterol Regulatory Element Binding Proteins/metabolism , Cholesterol/metabolism , Dose-Response Relationship, Drug , Hep G2 Cells , Homeostasis/drug effects , Humans , Phosphorylation/drug effects , Signal Transduction/drug effects , Structure-Activity RelationshipABSTRACT
A series of N-methoxyamide derivatives was identified and evaluated as GPR119 agonists. Several N-methoxyamides with thienopyrimidine and pyridine scaffolds showed potent GPR119 agonistic activities. Among them, compound 9c displayed good in vitro activity and potency. Moreover, compound 9c lowered glucose excursion in mice in an oral glucose tolerance test and increased GLP-1 secretion in intestinal cells.
Subject(s)
Amides/pharmacology , Drug Design , Receptors, G-Protein-Coupled/agonists , Amides/chemical synthesis , Amides/chemistry , Animals , Cell Line , Dose-Response Relationship, Drug , Glucagon-Like Peptide 1/metabolism , Glucose/administration & dosage , Glucose Tolerance Test , Humans , Intestinal Mucosa/metabolism , Intestines/cytology , Intestines/drug effects , Mice , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of thienopyrimidine derivatives was synthesized and evaluated for their GPR119 agonistic ability. Several thienopyrimidine derivatives containing R(1) and R(2) substituents displayed potent GPR119 agonistic activity. Among them, compound 5d, which is a prototype, showed good in vitro activity with an EC50 value of 3 nM and human and rat liver microsomal stability. Compound 5d exhibited no CYP inhibition and induction, Herg binding, or mutagenic potential. Compound 5d showed increase insulin secretion in beta TC-6 cell and lowered the glucose excursion in mice in an oral glucose-tolerance test.
