Advances in the development of covalent small molecule inhibitors of monoacylglycerol lipase / 生物工程学报

Monoacylglycerol lipase (MGL) is a serine hydrolase that plays a major role in the degradation of endogenous cannabinoid 2-arachidonoylglycerol. The role of MGL in some cancer cells has been confirmed, where inhibition of the MGL activity shows inhibition on cell proliferation. This makes MGL a promising drug target for the treatment of cancer. Recently, the development of covalent inhibitors of MGL has developed rapidly. These drugs have strong covalent binding ability, high affinity, long duration, low dose and low risk of drug resistance, so they have received increasing attention. This article introduces the structure and function of MGL, the characteristics, mechanisms and progress of covalent MGL inhibitors, providing reference for the development of novel covalent small molecule inhibitors of MGL.

Development of a highly-specific

As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified

Monoacylglycerol lipase high expression as an independent indicator of survival for patients with hepatocellular carcinoma / 中华肝脏病杂志

Objective@#To study the expression level of monoacylglycerol lipase (MAGL) in liver tissues of patients with hepatocellular carcinoma (HCC), and its clinical correlation.@*Methods@#Immunohistochemistry was employed to detect MAGL protein in 353 cases with hepatocellular carcinoma (HCC) and tissue microarray (TMA) for paracancerous liver tissues. The expression levels of MAGL in TMA were quantitatively analyzed using Image-Pro plus 6.0. The difference in MAGL expression between liver cancer tissues and paracancerous liver tissues was compared. Combined with the clinical follow-up data of TMA patients, the correlation between the expression of MAGL in TMA and the degree of HCC tumors differentiation and the survival rate of 1-year and 3-year were analyzed using Logistic regression analysis. The survival curves of patients with different levels of MAGL protein was plotted and analyzed using Kaplan-Meier method. The expression of MAGL protein was analyzed by multiple linear regression analysis. COX regression was used to analyze the correlation between MAGL protein expression level and the risk of HCC death in the included patients.@*Results@#The expression of MAGL in HCC tissues was significantly higher than paracancerous liver tissues. The expression level of MAGL was correlated to the degrees of HCC tumors differentiation (P < 0.001) and 1-year survival rate (P = 0.01), but not with 3-year survival rate (P = 0.91). Survival curve showed that the expression level of MAGL was negatively correlated with prognosis and survival of HCC patients (P = 0.001). Multiple linear regressions showed a negative correlation between MAGL expression level and overall survival time of HCC patients (P=0.010, R2=0.166, Durbin-Watson value: 1.989). COX regression showed that the expression of MAGL was a risk factor for death of patients with HCC [P = 0.004, Exp (B) = 1.000].@*Conclusion@#The expression level of MAGL has positive correlation with the malignant degree in HCC patients, and negative correlation with its prognosis. Therefore, MAGL may serve as a new prognostic indicator for HCC patients.

Effect of monoacylglycerol lipase with proliferation of MHCC97H human liver cancer cells in vivo / 中华肝脏病杂志

Objective@#To investigate the effects of different expression of monoacylglycerol lipase (MAGL) in tumor-associated macrophages (TAMs) with the proliferation of MHCC97H human liver cancer cells in vivo and its mechanism.@*Methods@#Human peripheral blood-derived monocyte was induced to differentiate into M2-type TAMs and was identified by flow cytometry. The co-culture model of TAMs and MHCC97H human liver cancer cells was established, and the expression of MAGL in TAMs cells was detected by qRT-PCR. The expression of MAGL in TAMs cells was detected by plasmid transfection. ELISA and qRT-PCR was used to detect the mRNA expression levels and secretion levels of inflammatory factors in TAMs cells. The subcutaneous tumor model of MHCC97H mice was constructed to observe the effect of different expression of MAGL in TAMs cells with the proliferation of MHCC97H human liver cancer cells in vivo. F-test was used for the measurement of homogeneity of variance between two independent samples. A t-test was used for homogeneity of variance, and the corrected t-test was used for non-homogeneity of variance.@*Results@#Human peripheral blood-derived monocytes were successfully induced to differentiate into M2-type TAMs. An in vitro co-culture model was established. qRT-PCR showed that MHCC97H human liver cancer cells significantly down-regulated the expressional level of MAGL in TAMs cells. The constructed subcutaneous tumor model of mice demonstrated that up-regulation up-regulation of MAGL expression in M2-type TAMs inhibited the proliferation of MHCC97H human liver cancer cells in vivo. Furthermore, the mechanistic study illustrated that the high expression of MAGL promoted the transcription and secretion of inflammatory factors such as interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha in M2-type TAMs cells.@*Conclusion@#The overexpression of MAGL inhibits the proliferation of MHCC97H hepatocellular carcinoma cells in vivo, and its mechanism may be associated to the release of inflammatory factors that from TAMs cells.

Preliminary screening and study of novel flavonoid monoacylglycerol lipase inhibitors / 上海交通大学学报（医学版）

Objective: To discover and develop novel monoacylglycerol lipase (MAGL) inhibitors. Methods: Computational screening, rational structure analysis and biological assessment was used. Results: A series of natural flavonoid MAGL inhibitors were identified. Compound 9 (quercetin) presented the highest activity with an IC50 value of 36 μmol/L. Conclusion: Several natural flavonoid MAGL inhibitors were identified, which are expected to bring novel hits for discovery of MAGL inhibitors.

Preliminary screening and study of novel flavonoid monoacylglycerol lipase inhibitors / 上海交通大学学报（医学版）

Objective·To discover and develop novel monoacylglycerol lipase (MAGL) inhibitors.Methods·Computational screening,rational structure analysis and biological assessment was used.Results·A series of natural flavonoid MAGL inhibitors were identified.Compound 9 (quercetin) presented the highest activity with an IC50 value of 36 μmol/L.Conclusion·Several natural flavonoid MAGL inhibitors were identified,which are expected to bring novel hits for discovery ofMAGL inhibitors.

Lipolysis and lipases in white adipose tissue – An update

Lipolysis is defined as the sequential hydrolysis of triacylglycerol (TAG) stored in cell lipid droplets. For many years, it was believed that hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MGL) were the main enzymes catalyzing lipolysis in the white adipose tissue. Since the discovery of adipose triglyceride lipase (ATGL) in 2004, many studies were performed to investigate and characterize the actions of this lipase, as well as of other proteins and possible regulatory mechanisms involved, which reformulated the concept of lipolysis. Novel findings from these studies include the identification of lipolytic products as signaling molecules regulating important metabolic processes in many non-adipose tissues, unveiling a previously underestimated aspect of lipolysis. Thus, we present here an updated review of concepts and regulation of white adipocyte lipolysis with a special emphasis in its role in metabolism homeostasis and as a source of important signaling molecules.