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1.
Acta Pharmacol Sin ; 42(1): 149-159, 2021 Jan.
Article in English | MEDLINE | ID: mdl-32451413

ABSTRACT

High infiltration of M2-polarized macrophages in the primary tumor indicates unfavorable prognosis and poor overall survival in the patients with triple-negative breast cancer (TNBC). Thus, reversing M2-polarized tumor-associated macrophages in the tumors has been considered as a potential therapeutic strategy for TNBC. Sphingomyelin synthase 2 (SMS2) is the key enzyme for sphingomyelin production, which plays an important role in plasma membrane integrity and function. In this study we investigated whether SMS2 inhibitor or SMS2 gene knockout could reduce macrophages M2 polarization and tumor progression in a mouse model of TNBC. We showed that SMS2 mRNA expression was linked to immunosuppressive tumor microenvironment and poor prognosis in TNBC patients. The knockout of SMS2 or application of 15w (a specific SMS2 inhibitor) markedly decreased the generation of M2-type macrophages in vitro, and reduced the tumor weight and lung metastatic niche formation in a 4T1-TNBC mouse model. We further demonstrated that the in vivo antitumor efficacy of 15w was accompanied by a multifaceted remodeling of tumor immune environment reflecting not only the suppression of M2-type macrophages but also diminished levels of regulatory T cells and myeloid-derived suppressor cells leading to a dramatically improved infiltration of antitumor CD8+ T lymphocytes. Collectively, our results reveal a novel and important role of SMS2 in the protumorigenic function and may offer a new strategy for macrophage-targeted anticancer therapy.


Subject(s)
Macrophages/metabolism , Transferases (Other Substituted Phosphate Groups)/metabolism , Triple Negative Breast Neoplasms/physiopathology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Disease Progression , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Gene Knockout Techniques , Humans , Immunity, Cellular/drug effects , Isoxazoles/pharmacology , Isoxazoles/therapeutic use , Macrophage Activation/drug effects , Macrophage Activation/physiology , Macrophages/drug effects , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Prognosis , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Transferases (Other Substituted Phosphate Groups)/genetics , Triple Negative Breast Neoplasms/diagnosis , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/immunology
2.
ACS Chem Biol ; 15(3): 632-639, 2020 03 20.
Article in English | MEDLINE | ID: mdl-32069008

ABSTRACT

Post-translational modifications play vital roles in fine-tuning a myriad of physiological processes, and one of the most important modifications is acetylation. Here, we report a ligand-directed site-selective acetylation using KHAc, a derivative of a phosphoglycerate mutase 1 (PGAM1) inhibitor. KHAc binds to PGAM1 and transfers its acetyl group to the ε-NH2 of Lys100 to inactivate the enzyme. The acetyl transfer process was visualized by time-resolved crystallography, demonstrating that the transfer is driven by proximity effects. KHAc was capable of selectively and effectively acetylating Lys100 of PGAM1 in cultured human cells, accompanied by inhibited F-actin formation. Similar strategies could be used for exogenous control of other lysine post-translational modifications.


Subject(s)
Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Phosphoglycerate Mutase/chemistry , Acetylation , Actins/metabolism , Binding Sites , Cell Proliferation/drug effects , Crystallization , HEK293 Cells , Humans , Ligands , Mutation , Phosphoglycerate Mutase/antagonists & inhibitors , Protein Binding , Protein Conformation , Protein Processing, Post-Translational
3.
Pharmazie ; 74(9): 553-558, 2019 09 01.
Article in English | MEDLINE | ID: mdl-31484596

ABSTRACT

Insulin resistance is a typical precursor and primary feature of type 2 diabetes mellitus (T2DM). Sphingomyelin (SM) is a kind of sphingolipid located in animal brain, liver, kidney and muscle. Sphingomyelin synthase 2 (SMS2) is the key enzyme in the synthesis of sphingomyelin, inhibition of which shows protective effects on cardiovascular and glucose metabolism. We used Ly93, a selective sphingomyelin synthase 2 inhibitor, to investigate the effect of SMS2 inhibitor on insulin resistance in vitro and in vivo. Our previous studies have shown that Ly93 is able to dose-dependently inhibit the SMS activity and attenuate the atherosclerotic lesions in apoE knock out mice. In this present study, we found that high fat diet (HFD) induced insulin-resistant C57BL/6 mice treated with Ly93 were more sensitive to insulin than untreated mice, and presented lower blood insulin levels and improved insulin tolerance. Furthermore, insulin signal pathway related protein levels were detected by western blot, which indicated that SMS2 inhibitor significantly upregulated the phosphorylation of IRS-1, Akt and GSK-3ß, thus enhanced the insulin signaling. In vitro, Ly93 enhanced the phosphorylation of Akt in HepG2 cells, which was reversed by exogenous sphingomyelin. These results suggest that SMS2 inhibitor could ameliorate insulin resistance via regulating the insulin signaling. Our findings support that SMS2 is a potential target for insulin resistance.


Subject(s)
Enzyme Inhibitors/pharmacology , Insulin Resistance , Insulin/blood , Membrane Proteins/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Organic Chemicals/pharmacology , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Animals , Diet, High-Fat , Glycogen Synthase Kinase 3 beta/metabolism , Hep G2 Cells , Humans , Insulin Receptor Substrate Proteins/metabolism , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Sphingomyelins/metabolism , Transferases (Other Substituted Phosphate Groups)/metabolism
5.
Eur J Med Chem ; 163: 864-882, 2019 Feb 01.
Article in English | MEDLINE | ID: mdl-30580239

ABSTRACT

The sphingomyelin synthase 2 (SMS2) is a potential target for pharmacological intervention in atherosclerosis. However, so far, few selective SMS2 inhibitors and their pharmacological activities were reported. In this study, a class of 2-benzyloxybenzamides were discovered as novel SMS2 inhibitors through scaffold hopping and structural optimization. Among them, Ly93 as one of the most potent inhibitors exhibited IC50 values of 91 nM and 133.9 µM against purified SMS2 and SMS1 respectively. The selectivity ratio of Ly93 was more than 1400-fold for purified SMS2 over SMS1. The in vitro studies indicated that Ly93 not only dose-dependently diminished apoB secretion from Huh7 cells, but also significantly reduced the SMS activity and increased cholesterol efflux from macrophages. Meanwhile, Ly93 inhibited the secretion of LPS-mediated pro-inflammatory cytokine and chemokine in macrophages. The pharmacokinetic profiles of Ly93 performed on C57BL/6J mice demonstrated that Ly93 was orally efficacious. As a potent selective SMS2 inhibitor, Ly93 significantly decreased the plasma SM levels of C57BL/6J mice. Furthermore, Ly93 was capable of dose-dependently attenuating the atherosclerotic lesions in the root and the entire aorta as well as macrophage content in lesions, in apolipoprotein E gene knockout mice treated with Ly93. In conclusion, we discovered a novel selective SMS2 inhibitor Ly93 and demonstrated its anti-atherosclerotic activities in vivo. The preliminary molecular mechanism-of-action studies revealed its function in lipid homeostasis and inflammation process, which indicated that the selective inhibition of SMS2 would be a promising treatment for atherosclerosis.


Subject(s)
Atherosclerosis/drug therapy , Benzamides/therapeutic use , Drug Discovery , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Animals , Apolipoproteins E/genetics , Benzamides/chemistry , Benzamides/pharmacology , Cell Line , Homeostasis/drug effects , Humans , Inflammation/drug therapy , Lipid Metabolism , Macrophages/metabolism , Mice , Mice, Knockout
6.
J Biol Chem ; 293(47): 18328-18336, 2018 11 23.
Article in English | MEDLINE | ID: mdl-30305392

ABSTRACT

2-Hydroxy-oleic acid (2OHOA) is a potent anticancer drug that induces cancer cell cycle arrest and apoptosis. Previous studies have suggested that 2OHOA's anticancer effect is mediated by SMS activation in cancer cells, including A549 and U118 cells. To confirm this phenomenon, in this study, we treated both A549 and U118 cells with 2OHOA and measured SMS activity. To our surprise, we found neither 2OHOA-mediated SMS activation nor sphingomyelin accumulation in the cells. However, we noted that 2OHOA significantly reduces phosphatidylcholine in these cells. We also did not observe 2OHOA-mediated SMS activation in mouse tissue homogenates. Importantly, 2OHOA inhibited rather than activated recombinant SMS1 (rSMS1) and rSMS2 in a dose-dependent fashion. Intra-gastric treatment of C57BL/6J mice with 2OHOA for 10 days had no effects on liver and small intestine SMS activities and plasma sphingomyelin levels. The treatment inhibited lysophosphatidylcholine acyltransferase (LPCAT) activity, consistent with the aforementioned reduction in plasma phosphatidylcholine. Because total cellular phosphatidylcholine is used as a predictive biomarker for monitoring tumor responses, the previously reported 2OHOA-mediated cancer suppression could be related to this phosphatidylcholine reduction, which may influence cell membrane structure and properties. We conclude that 2OHOA is not a SMS activator and that its anticancer property may be related to an effect on phosphatidylcholine metabolism.


Subject(s)
Antineoplastic Agents/metabolism , Neoplasms/enzymology , Oleic Acids/metabolism , Transferases (Other Substituted Phosphate Groups)/metabolism , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Cell Line, Tumor , Enzyme Activation , Enzyme Activators/administration & dosage , Enzyme Activators/chemistry , Enzyme Activators/metabolism , Humans , Mice , Mice, Inbred C57BL , Neoplasms/drug therapy , Neoplasms/genetics , Neoplasms/metabolism , Oleic Acids/administration & dosage , Oleic Acids/chemistry , Phosphatidylcholines/metabolism , Sphingomyelins/metabolism , Transferases (Other Substituted Phosphate Groups)/chemistry , Transferases (Other Substituted Phosphate Groups)/genetics
7.
J Med Chem ; 61(18): 8241-8254, 2018 09 27.
Article in English | MEDLINE | ID: mdl-30074791

ABSTRACT

Sphingomyelin synthase 2 (SMS2) is a promising therapeutic target for several chronic inflammation-associated diseases, including atherosclerosis, fatty liver, and insulin resistance. Herein, we report the identification of 4-benzyloxybenzo[ d]isoxazole-3-amine derivatives as potent and highly selective SMS2 inhibitors through a conformational restriction strategy. After systematic structural modifications, several compounds with high selectivity and good potency in vitro were selected for further evaluation. Compound 15w demonstrated good pharmacokinetics (oral bioavailability, F = 56%) in vivo and has an inhibitory potency against sphingomyelin synthase activity when Institute of Cancer Research mice are provided with an oral dose of this compound. In addition, compound 15w attenuated chronic inflammation significantly in db/ db mice after oral dosing for 6 weeks.


Subject(s)
Amines/chemistry , Diabetes Mellitus, Experimental/drug therapy , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Inflammation/prevention & control , Membrane Proteins/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Animals , Diabetes Mellitus, Experimental/complications , Humans , Inflammation/etiology , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred ICR , Models, Molecular , Molecular Structure , Nerve Tissue Proteins/metabolism , Protein Conformation , Structure-Activity Relationship , Transferases (Other Substituted Phosphate Groups)/metabolism
8.
Bioorg Med Chem Lett ; 27(15): 3511-3515, 2017 08 01.
Article in English | MEDLINE | ID: mdl-28619536

ABSTRACT

Sphingomyelin synthase (SMS) is a key enzyme in sphingomyelin biosynthetic pathway, whose activity is highly related to the atherosclerosis progression. SMS2 could serve as a promising therapeutic target for atherosclerosis. Based on the structure of lead compound D2, a series of oxazolopyridine derivatives were designed, synthesized, and their inhibitory activities against purified SMS1 and SMS2 enzymes were evaluated respectively. The representative molecules QY4 and QY16 possess micromolar inhibitory activities against SMS2 and excellent isoform preferences over SMS1, qualified to be selected as potential molecules in further discovery of specific SMS2 inhibitors.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Membrane Proteins/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Transferases (Other Substituted Phosphate Groups)/antagonists & inhibitors , Drug Discovery , Humans , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Molecular Docking Simulation , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/metabolism , Oxazoles/chemistry , Oxazoles/pharmacology , Transferases (Other Substituted Phosphate Groups)/chemistry , Transferases (Other Substituted Phosphate Groups)/metabolism
9.
J Med Chem ; 59(6): 2674-87, 2016 Mar 24.
Article in English | MEDLINE | ID: mdl-26927682

ABSTRACT

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.


Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/antagonists & inhibitors , Diabetic Retinopathy/drug therapy , Macular Edema/drug therapy , Phospholipase A2 Inhibitors/chemical synthesis , Animals , Caco-2 Cells , Cell Membrane/metabolism , Diabetes Mellitus, Experimental/pathology , Drug Discovery , Humans , Liver/metabolism , Macular Edema/etiology , Male , Mice , Phospholipase A2 Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Retina/pathology , Structure-Activity Relationship
10.
J Med Chem ; 58(21): 8529-41, 2015 Nov 12.
Article in English | MEDLINE | ID: mdl-26479945

ABSTRACT

Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.


Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , 1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , Administration, Oral , Animals , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Male , Mice , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
11.
Bioorg Med Chem Lett ; 25(21): 4724-4727, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26320622

ABSTRACT

The zinc metalloenzyme glyoxalase I (GlxI) catalyzes the glutathione-dependent inactivation of cytotoxic methylglyoxal. Two competitive bivalent GlxI inhibitors, polyBHG2-62 (Ki=1.0 nM) and polyBHG2-54 (Ki=0.3 nM), were synthesized based on the transition-state analog S-(N-bromophenyl-N-hydroxycarbamoyl) glutathione (BHG). The most effective inhibitor, polyBHG2-54, is the first subnanomolar inhibitor of GlxI, and is over 50-fold more potent than BHG itself.


Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Lactoylglutathione Lyase/antagonists & inhibitors , Lactoylglutathione Lyase/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Humans , Molecular Structure , Structure-Activity Relationship
12.
Bioorg Med Chem Lett ; 23(10): 2897-901, 2013 May 15.
Article in English | MEDLINE | ID: mdl-23575276

ABSTRACT

This Letter reports our efforts towards the optimization of our previously identified series of imidazole and triazole derivatives that lead to the discovery of a series of orally active Lp-PLA2 inhibitors in C57 mice. These inhibitors are characterized by the presence of a diamine side chain in the molecules, such as 2c, 2f, and 4a. The introduction of the terminal-end amine succeeded in maintaining the in vitro activities at sub-nanomolar levels. The vivo activities could be greatly affected by variations in the two amines via modulating the metabolic stability and lipophilicity of the compounds.


Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/antagonists & inhibitors , Benzaldehydes/pharmacology , Enzyme Inhibitors/pharmacology , Oximes/pharmacology , 1-Alkyl-2-acetylglycerophosphocholine Esterase/blood , 1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , Administration, Oral , Animals , Benzaldehydes/administration & dosage , Benzaldehydes/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Mice , Mice, Inbred C57BL , Molecular Structure , Oximes/administration & dosage , Oximes/chemistry , Rabbits , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Structure-Activity Relationship
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