Discovery of XEN445: A potent and selective endothelial lipase inhibitor raises plasma HDL-cholesterol concentration in mice

Sun, Shaoyi; Dean, Richard A.; Jia, Qi; Zenova, Alla; Zhong, Jing; Grayson, Christopher; Xie, Clark; Lindgren, Andrea; Samra, Pritpaul; Sojo, Luis; Heek, Margaret van; Lin, Linus; Percival, David; Fu, Jinmin; Winther, Michael D.; Zhang, Zaihui

doi:10.1016/j.bmc.2013.10.023

Cited by 15 publications

(26 citation statements)

References 26 publications

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“…1D). Based on the linear regression equation, the predicted IC50 of XEN445 is 2.172 μM, which is approximately 9-fold higher than the reported IC50 (0.237 μM) of XEN445 8 . This difference may be due to a different approach used in the assay system.…”

Section: Resultsmentioning

confidence: 59%

“…XEN445 has shown to inhibit the phospholipase activity of LIPG ( Fig. 1A) 8 . To validate the inhibitory effect of XEN445 on the enzymatic activity of LIPG at a cellular level, we performed LIPG enzymatic assays using parental and LIPG-overexpressing MDA-MB-468 cell lines 16 .…”

Section: Resultsmentioning

confidence: 98%

“…Since our prior studies have shown that LIPG is essential for the malignancy and metastasis of TNBC 16 , it is clinically imperative to investigate the therapeutic effects of currently available chemical inhibitors targeting LIPG. In this study, we for the first time explored the therapeutic impacts of XEN445, a chemical inhibitor specific to the phospholipase activity of LIPG 8 , on TNBC malignancy. We first examined the effect and IC50 of XEN445 on LIPG phospholipase activity.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of LIPG phospholipase activity suppresses tumor formation of human basal-like triple-negative breast cancer

Yao

Zhou

2020

Sci Rep

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the endothelial lipase LipG possesses serine phospholipase activity and is involved in lipoprotein metabolism. our previous studies have revealed that LipG overexpression is required for tumor formation and metastasis of human basal-like triple-negative breast cancer (tnBc). We also demonstrated that LIPG differentially regulates TNBC malignancy through its enzymatic and nonenzymatic functions. The present studies were aimed at determining how XEN445, a specific inhibitor targeting LipG phospholipase activity, impacts on tnBc tumor formation and malignant features. We established a cell-based LIPG enzymatic assay system to measure the inhibitory effect of XEN445 on LIPG phospholipase activity and determine its IC50. We found that XEN445 preferentially inhibited the proliferation of LipG-expressing tnBc cells but not LipG-negative luminal breast cancer cells. XEN445 inhibited the self-renewal of cancer stem cells (CSCs) in vitro and tnBc tumor formation in vivo. However, XEN445 had no inhibitory effect on the invasiveness and CSC stemness of TNBC cells. Our studies suggest that targeting both LIPG enzymatic and non-enzymatic functions is an important strategy for the treatment of tnBc. Lipases control lipid metabolism by regulating the hydrolysis of neutral lipids to free fatty acids (FFAs) and glycerol. FFAs generated from lipolysis are imported into the cell for energy usage and storage, where lipases are critically involved in regulating energy homeostasis. This lipase-mediated lipolysis is critical for the breakdown of extracellular lipoproteins, triglycerides, and phospholipids. One of lipases is LIPG (also called endothelial lipase), which is encoded by the gene LIPG. LIPG, first identified in 1999 1,2 , is a member of the triglyceride lipase family and shares significant protein sequence homology (about 40% identity) with other triglyceride lipases 1,2. The LIPG protein sequence contains motifs (GXSXG, the heparin-binding motif, and the catalytic triad S169, D193, H274), which are critical for lipase activity 1,2. LIPG manifests predominant serine phospholipase activity when compared with other triglyceride lipases (e.g., lipoprotein lipase (LPL) and hepatic lipase (HL)) that mainly display triglyceride lipase activity 3,4. LIPG has shown to be responsible for the metabolism of several lipoproteins in vitro and in vivo, in particular high-density lipoprotein particles (HDL cholesterol) 3,4. Adenovirus-mediated overexpression of LIPG in LDL receptor-deficient mice resulted in the reduction of plasma VLDL and LDL cholesterol levels by about 50%. However, it almost depleted plasma HDL cholesterol levels, indicating that LIPG plays a critical role in HDL catabolism 1. HDL is known as "protective" cholesterol because having high HDL levels can reduce the risk of heart disease and stroke. Since LIPG can hydrolyze HDL phospholipids, the overabundance of LIPG leads to the lower circulating levels of HDL, which promotes heart disease. As blocking LIPG activity leads to an increase in total plasma HDL levels, inhibit...

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Section: Resultsmentioning

confidence: 59%

Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Inhibition of LIPG phospholipase activity suppresses tumor formation of human basal-like triple-negative breast cancer

Yao

Zhou

2020

Sci Rep

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“…Compound 3 showedg ood inhibition of LIPG (IC 50 = 237 nm) and demonstrated 500-and 40-folds electivity over LPL and LIPC, respectively.T he inhibitor also demonstratedi nv ivo efficacy showinge levated plasma HDL-C levels in mice. [24] More potent inhibitor classes were pyrimidone carboxamide compounds, devised in 2013 by Hu et al of Bristol-Myers-Squibb. Compound 4 exhibited high potencyf or LIPG (IC 50 = 11 nm), but selectivities towards other triglyceride lipases weren ot mentioned.…”

Section: Serum Lipasesmentioning

confidence: 99%

“…[ 22] in vitro 2L IPG XEN445 (3)237 nm ? [24] in vitro (mice) 3L IPG 4 11 nm covalent (?) [ 25] in vitro 4L IPG 5 < 10 nm covalent (?)…”

Section: Summary and Key Outstanding Questionsmentioning

confidence: 99%

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

et al. 2016

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The coordinated processes of lipid synthesis, degradation, and transport are mediated by enzymes, cofactors, and transport proteins. Accordingly, lipid-metabolizing enzymes represent logical targets for the treatment of dyslipidemia, a major risk factor for type 2 diabetes, atherosclerosis, and other disorders. Small-molecule tool compounds, modulating the functions of such proteins, can substantially facilitate the characterization of target proteins. Such molecules complement genetic studies, and allow time- and dose-dependent control of protein activity in biological systems. This can improve our understanding of physiological processes, give insights into the druggability of target proteins, and might finally result in the development of therapeutic compounds. In this review we summarize the current state of available inhibitors targeting key proteins in neutral lipid metabolism, with a focus on metabolic lipases, acyltransferases, and fatty-acid-binding proteins.

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Phase‐Separated Liposomes Hijack Endogenous Lipoprotein Transport and Metabolism Pathways to Target Subsets of Endothelial Cells In Vivo

Arias-Alpizar

Papadopoulou

Rios

et al. 2023

Adv Healthcare Materials

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Plasma lipid transport and metabolism are essential to ensure correct cellular function throughout the body. Dynamically regulated in time and space, the well‐characterized mechanisms underpinning plasma lipid transport and metabolism offers an enticing, but as yet underexplored, rationale to design synthetic lipid nanoparticles with inherent cell/tissue selectivity. Herein, a systemically administered liposome formulation, composed of just two lipids, that is capable of hijacking a triglyceride lipase‐mediated lipid transport pathway resulting in liposome recognition and uptake within specific endothelial cell subsets is described. In the absence of targeting ligands, liposome‐lipase interactions are mediated by a unique, phase‐separated (“parachute”) liposome morphology. Within the embryonic zebrafish, selective liposome accumulation is observed at the developing blood‐brain barrier. In mice, extensive liposome accumulation within the liver and spleen – which is reduced, but not eliminated, following small molecule lipase inhibition – supports a role for endothelial lipase but highlights these liposomes are also subject to significant “off‐target” by reticuloendothelial system organs. Overall, these compositionally simplistic liposomes offer new insights into the discovery and design of lipid‐based nanoparticles that can exploit endogenous lipid transport and metabolism pathways to achieve cell selective targeting in vivo.

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Discovery of XEN445: A potent and selective endothelial lipase inhibitor raises plasma HDL-cholesterol concentration in mice

Cited by 15 publications

References 26 publications

Inhibition of LIPG phospholipase activity suppresses tumor formation of human basal-like triple-negative breast cancer

Inhibition of LIPG phospholipase activity suppresses tumor formation of human basal-like triple-negative breast cancer

Chemical Genetic Approaches for the Investigation of Neutral Lipid Metabolism

Phase‐Separated Liposomes Hijack Endogenous Lipoprotein Transport and Metabolism Pathways to Target Subsets of Endothelial Cells In Vivo

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