Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity

Hong, Lan; Cheng, Cliff C.; Kowalski, Timothy J.; Pang, Lei; Shan, Lianwei; Chuang, Chiashain; Jackson, James G.; Rojas-Triana, Alberto; Bober, Loretta A.; Liu, Li; Voigt, Johannes H.; Orth, Peter; Xiao-lin, Yang; Shipps, Gerald W.; Hedrick, Joseph A.

doi:10.1194/jlr.m012757

Cited by 78 publications

(68 citation statements)

References 34 publications

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“…In agreement with findings in ob/ob mice [35], the AFABP inhibitor reduces plasma triacylglycerol (TG) levels [36]. However, insulin and glucose tolerance are not improved by AFABP inhibition in DIO mice [36], in contrast to findings in ob/ob animals [35]. In agreement with these findings, knockdown of AFABP mediated by RNA interference technology does not significantly influence glucose homeostasis in DIO mice, but these mice significantly increase in body weight compared with vehicle-treated controls [37].…”

Section: Production and Structure Of Afabpsupporting

confidence: 71%

“…Concerning beta cell function, islet and pancreas morphology are not affected by the AFABP inhibitor [35]. BMS309403 has also been studied in DIO mice [36]. In agreement with findings in ob/ob mice [35], the AFABP inhibitor reduces plasma triacylglycerol (TG) levels [36].…”

Section: Production and Structure Of Afabpsupporting

confidence: 61%

“…BMS309403 has also been studied in DIO mice [36]. In agreement with findings in ob/ob mice [35], the AFABP inhibitor reduces plasma triacylglycerol (TG) levels [36]. However, insulin and glucose tolerance are not improved by AFABP inhibition in DIO mice [36], in contrast to findings in ob/ob animals [35].…”

Section: Production and Structure Of Afabpmentioning

confidence: 54%

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Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

2012

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Adipocyte fatty acid binding protein (AFABP, also known as aP2 and FABP4) has recently been introduced as a novel fat-derived circulating protein. AFABP serum concentrations are positively correlated with markers of the metabolic syndrome and vascular disease in various cross-sectional and interventional studies. Furthermore, a small set of prospective studies indicates that high AFABP serum levels at baseline predict the risk for metabolic and vascular morbidity and mortality. Studies in Afabp (also known as Fabp4) knockout mice and AFABP inhibitortreated animals suggest that total AFABP promotes insulin resistance, hypertriacylglycerolaemia and atherosclerosis by ligand/ligand delivery, as well as ligand-independent mechanisms. In contrast, the pathophysiological significance of circulating AFABP and the mechanisms leading to its release remain to be established. The current review summarises recent findings on the regulation and potential role of AFABP in metabolic and vascular disease.

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Section: Production and Structure Of Afabpsupporting

confidence: 71%

Section: Production and Structure Of Afabpsupporting

confidence: 61%

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Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

2012

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“…Additionally, several synthetic FABP4 inhibitors have been developed to date (Lehmann et al 2004, Ringom et al 2004, Sulsky et al 2007, Furuhashi & Hotamisligil 2008, Barf et al 2009, Hertzel et al 2009, Lan et al 2011, Xu et al 2012, Chen et al 2014. Among them, BMS309403, an active small molecule that impedes the binding of FAs to the FABP4 FA-binding cavity (Furuhashi et al 2007, Sulsky et al 2007, Furuhashi & Hotamisligil 2008, has been shown in several experimental models to protect against insulin resistance, diabetes mellitus, fatty liver disease and atherosclerosis (Furuhashi et al 2007, Lee et al 2011.…”

Section: :3mentioning

confidence: 99%

Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease

Rodríguez-Calvo¹,

Girona²,

Alegret

et al. 2017

Journal of Endocrinology

100

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Obesity and ectopic fat accumulation in non-adipose tissues are major contributors to heart failure (HF) and cardiovascular disease (CVD). Adipocytes act as endocrine organs by releasing a large number of bioactive molecules into the bloodstream, which participate in a communication network between white adipose tissue and other organs, including the heart. Among these molecules, fatty acid-binding protein 4 (FABP4) has recently been shown to increase cardiometabolic risk. Both clinical and experimental evidence have identified FABP4 as a relevant player in atherosclerosis and coronary artery disease, and it has been directly related to cardiac alterations such as left ventricular hypertrophy (LVH) and both systolic and diastolic cardiac dysfunction. The available interventional studies preclude the establishment of a direct causal role of this molecule in CVD and HF and propose FABP4 as a biomarker rather than as an aetiological factor. However, several experimental reports have suggested that FABP4 may act as a direct contributor to cardiac metabolism and physiopathology, and the pharmacological targeting of FABP4 may restore some of the metabolic alterations that are conducive to CVD and HF. Here, we review the current knowledge regarding FABP4 in the context of HF and CVD as well as the molecular basis by which this protein participates in the regulation of cardiac function.

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“…Additional substitution of a methyl (18) or methoxy (19) group at the meta position resulted in a potency decrease of 7-fold. Bridging the two oxygen atoms at the 3-and 4-position of the phenyl group through either one carbon (20) or three carbons (21) gave compounds with potency 2-fold less than compound 1. Interestingly, pronounced improvements in potency and selectivity against CDK2 were observed when the phenyl group was substituted with a para-phenoxy group (22).…”

mentioning

confidence: 99%

Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

Huang

Cheng

Fischmann

et al. 2012

ACS Med. Chem. Lett.

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A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection−mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2.KEYWORDS: affinity selection−mass spectrometry (AS-MS), Automated Ligand Identification System (ALIS), CHK1 protein kinase, structure-based drug design, thiazole-4-carboxamide C ancer is the leading cause of death globally. 1 Among the treatments used in cancer clinics, DNA-damaging chemotherapies have received widespread use despite their severe side effects on highly proliferative tissues and vulnerability to drug resistance. 2 There is an urgent need in cancer therapy for improved tolerability and longer lasting efficacy. When cells are exposed to agents that induce DNA damage, DNA repair pathways are activated by arresting at various cell cycle check points, G1, S, and G2/M. 3 While normal cells could arrest in the G1 phase through the tumor suppressor protein p53, most cancer cells lack this option because of p53 mutations and will have to rely on the S or G2/M checkpoint for DNA repair and survival. Such reliance in p53 mutant cancer cells would offer a significant opportunity for targeted cancer therapy. 4 CHK1 (checkpoint kinase 1) is a serine/threonine kinase and the key mediator in S and G2/M checkpoints. 5 The abrogation of CHK1 and the remaining checkpoints consequentially will cause cancer cells with DNA damage premature entry into mitosis and result in cell death. 6 Therefore, an enlarged therapeutic window would be expected in anticancer therapies utilizing a combination of a DNA-damaging agent with a CHK1 inhibitor.Over the past years, extensive research efforts in CHK1 inhibition have been undertaken in oncology. Several small molecule CHK1 inhibitors have been discovered and entered into clinical trials. 7−11 In our efforts to discover novel small molecule CHK1 inhibitors, the AS-MS ALIS (affinity selection−mass spectrometry-based Automated Ligand Identification System) platform was used to identify hits from mixture-based combinatorial libraries. 12 ALIS has demonstrated its unique capability in screening label-free mixture-based libraries and finding hits that were subsequently developed into lead compounds in various classes of protein targets, including the anti-infective target Escherichia coli dihydrofolate reductase, 13 antibacterial AccC (acetyl coenzyme-A carboxylase), 14 HCV NS5B (hepatitis C virus nonstructural protein 5B) polymerase, 15−17 protein kinase CDK2 (cyclin-dependent kinase 2), 18 KSP (kinesin spindle protein) in oncology, 19 FABP4 (fatty acid binding protein-4) 20 and the lipid phosphatase SHIP2 (SH2 domain-containing inositol 5-phosphatase 2) 21 in diabetes, MK2 (mitogen-activated protein ...

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Small-molecule inhibitors of FABP4/5 ameliorate dyslipidemia but not insulin resistance in mice with diet-induced obesity

Cited by 78 publications

References 34 publications

Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

Role of the fatty acid-binding protein 4 in heart failure and cardiovascular disease

Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

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