更新于：2024-11-01

hMELK

更新于：2024-11-01

基本信息

别名

hMELK、hPK38、KIAA0175

+ [6]

简介

Serine/threonine-protein kinase involved in various processes such as cell cycle regulation, self-renewal of stem cells, apoptosis and splicing regulation. Has a broad substrate specificity; phosphorylates BCL2L14, CDC25B, MAP3K5/ASK1 and ZNF622. Acts as an activator of apoptosis by phosphorylating and activating MAP3K5/ASK1. Acts as a regulator of cell cycle, notably by mediating phosphorylation of CDC25B, promoting localization of CDC25B to the centrosome and the spindle poles during mitosis. Plays a key role in cell proliferation and carcinogenesis. Required for proliferation of embryonic and postnatal multipotent neural progenitors. Phosphorylates and inhibits BCL2L14, possibly leading to affect mammary carcinogenesis by mediating inhibition of the pro-apoptotic function of BCL2L14. Also involved in the inhibition of spliceosome assembly during mitosis by phosphorylating ZNF622, thereby contributing to its redirection to the nucleus. May also play a role in primitive hematopoiesis.

关联

项与 hMELK 相关的药物

OTS-167

靶点

hMELK

作用机制

MELK抑制剂

在研机构

OncoTherapy Science, Inc.

原研机构

OncoTherapy Science, Inc.

在研适应症

晚期乳腺癌 [+2]

非在研适应症

急性淋巴细胞白血病 [+7]

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

ARN-0953

靶点

hMELK

作用机制

MELK抑制剂

在研机构

Arrien Pharmaceuticals LLC

原研机构

Arrien Pharmaceuticals LLC

在研适应症

血液肿瘤

非在研适应症-

最高研发阶段早期临床1期

首次获批国家/地区-

首次获批日期1800-01-20

SLX 0953

靶点

FLT3 x hMELK

作用机制

FLT3调节剂 [+1]

在研机构

Signalexis, Inc.

原研机构

Signalexis, Inc.

在研适应症

急性髓性白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 hMELK 相关的临床试验

JPRN-jRCT2031230090 / Recruiting临床1期IIT

A Phase I Study of OTS167PO, a MELK inhibitor, to Evaluate Safety, Tolerability and Pharmacokinetics in Patients with Advanced Breast Cancer and Dose-Expansion Study in Patients with Triple Negative Breast Cancer. - OTS1070103

开始日期2021-03-02

申办/合作机构-

NCT02926690 / Recruiting临床1期

A Phase I Study of OTS167PO, a MELK Inhibitor, to Evaluate Safety, Tolerability and Pharmacokinetics in Patients With Advanced Breast Cancer and Dose-Expansion Study in Patients With Triple Negative Breast Cancer

The purpose of this study is to determine the maximum tolerated dose (MTD) of OTS167 administered via oral capsule (PO) to patients with relapsed/refractory locally advanced or metastatic breast cancer.

开始日期2017-05-29

申办/合作机构

OncoTherapy Science, Inc.

ACTRN12616000043437 / Completed临床1期IIT

A phase 1, randomised, placebo-controlled, double-blind, cross-over study to evaluate systemic bioavailability of oral OTS167 under fed and fasting conditions in healthy adult subjects.

开始日期2016-01-11

申办/合作机构-

100 项与 hMELK 相关的临床结果

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100 项与 hMELK 相关的转化医学

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0 项与 hMELK 相关的专利（医药）

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383

项与 hMELK 相关的文献（医药）

2024-09-01·Theriogenology

Transcriptome analysis reveals hepatic disordered lipid metabolism, lipotoxic injury, and abnormal development in IUGR sheep fetuses due to maternal undernutrition during late pregnancy

Article

作者: Xu, Xiaoyi ; Qin, Yulong ; Gao, Feng ; Yang, Yilin ; Zi, Yang ; Ma, Chi ; Li, Mingyue ; He, Qiuyue ; Liu, Yingchun ; Qiao, Yina

Although lipid metabolism in fetal livers under intrauterine growth restriction (IUGR) conditions has been widely studied, the implications of maternal undernutrition on fetal hepatic lipid metabolism, lipotoxic injury, and abnormal development remain largely unknown. Therefore, this study investigated the effects of maternal undernutrition on disordered hepatic lipid metabolism, lipotoxic injury, and abnormal development in IUGR sheep fetuses using transcriptome analysis. Seventeen singleton ewes were randomly divided into three groups on day 90 of pregnancy: a control group (CG; 0.63 MJ metabolic energy/body weight (ME/BW)^0.75/day, n = 5), maternal undernutrition group 1 (MU1; 0.33 MJ ME/BW^0.75/day, n = 6), and maternal undernutrition group 2 (MU2; 0.20 MJ ME/BW^0.75/day, n = 6). The fetuses were euthanized and recovered on day 130 of pregnancy. The levels of free fatty acids (FFA) in maternal blood (P < 0.01), fetal blood (P < 0.01), and fetal livers (P < 0.05) were increased in the MU1 and MU2 groups, but fetal hepatic triglyceride (TG) levels in the MU2 group (P < 0.01) and β-hydroxybutyrate levels in the MU1 and MU2 groups (P < 0.01) were decreased compared to the CG. Severe inflammatory cell infiltration and increased non-alcoholic fatty liver disease activity scores were observed in MU1 and MU2 fetuses (P < 0.01). Progressive deposition of fetal hepatic reticular fibers and collagen fibers in the fetal livers of the MU1 and MU2 groups and significant hepatic fibrosis were observed in the MU2 fetuses (P < 0.05). Gene set enrichment analysis showed that genes involved in lipid accumulation and FFA beta oxidation were downregulated in both MU groups compared to those in the controls. The fetal liver mRNA expression of the β-oxidation regulator, acetyl-CoA acetyltransferase 1, and the TCA regulator, isocitrate dehydrogenase were reduced in MU1 (P < 0.05) and MU2 (P < 0.01) fetuses, and downregulated mRNA expression of long chain fatty acid CoA ligase 1 (P < 0.05) and glycerol-3-phosphate acyltransferase (P < 0.01) was observed in MU2 fetuses. Differentially expressed genes (DEGs) in MU1 versus CG (360 DEGs) and MU2 versus CG (746 DEGs) were identified using RNA sequencing. Bioinformatics analyses of the 231 intersecting DEGs between MU1 versus CG and MU2 versus CG indicated that neutrophil extracellular traps (NETs) were induced and played a central role in fetal hepatic injury in IUGR sheep. Increased maternal blood myeloperoxidase (MPO) levels (P < 0.01), NE (Elane)-positive areas in fetal liver sections (P < 0.05), and fetal liver MPO protein expression (P < 0.01) were found in the MU1 and MU2 groups; however, MPO levels were reduced in the fetal membrane (P < 0.01) and fetal blood (P < 0.05) in the MU1 group, and in the maternal-fetal placenta and fetal blood in the MU2 group (P < 0.01). Analysis of gene expression trends in the intersecting DEGs between MU1 versus CG (129 DEGs) and MU2 versus CG (515 DEGs) further revealed that 30 hub genes were essential regulators of the G2/M cell cycle, all of which were associated with hepatocellular carcinoma. G0/G1 phase cells of the fetal liver were reduced in the MU1 (P < 0.05) and MU2 (P < 0.01) groups, whereas G2/M phase cells were elevated in the MU1 and MU2 groups (P < 0.01). The representatives of upregulated hub genes and fetal liver protein expression of maternal embryonic leucine zipper kinase and protein regulator of cytokinesis 1 were progressively enhanced in the MU1 and MU2 groups (P < 0.01), and topoisomerase II alpha protein expression in the MU2 group (P < 0.05), as expected. These results indicate that FFA overload, severe lipotoxic injury, and NETs were induced, and disease-promoting regulators of the G2/M cell cycle were upregulated in the fetal liver of IUGR sheep. These findings provide new insights into the pathogenesis of impaired hepatic lipid metabolism and abnormal development and the molecular origin of post-natal liver disease in IUGR due to maternal undernutrition. This information can support the development of new therapeutic strategies.

2024-06-01·Translational Oncology

Hsa_circ_0101050 accelerates the progression of Colon cancer by targeting the miR-140–3 p/MELK axis

Article

作者: Chen, Bin ; Huang, Wei ; Zhao, Ting ; Chen, Hao ; Fan, Caibo ; Cheng, Kuoju ; Yan, Huan ; Li, Jing ; Peng, Lei ; Luo, Yun

BACKGROUNDCircular RNAs (circRNAs) are involved in the progression of colon cancer (CC). This study aimed to examine the role of a new circRNA circ_0101050 in CC.METHODSDual-luciferase reporter and RNA immunoprecipitation analyses were performed to validate the target relationships among maternal embryonic leucine zipper kinase (MELK), microRNA (miR)-140-3 p, and circ_0101050. Expression levels were calculated using western blotting and/or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Western blotting was performed to evaluate the relative expression of Bcl-2 and Bax proteins to determine cell death. Cell Counting Kit-8 (CCK-8) and colony formation assays were performed to determine the proliferative potential of CC cells. The migration rate of CC cells was evaluated using wound healing assays. Tumor formation tests were performed to determine the effect of circ_0101050 on tumor development in vivo.RESULTSElevated levels of circ_0101050 and MELK were observed in CC. By inhibiting circ 0,101,050 or MELK, CC cell proliferation and migration were inhibited, but CC cell apoptosis was promoted. Silencing circ_0101050 also inhibited CC growth in vivo. We also found that miR-140-3 p was downregulated, which alleviated the repressive effects of circ_0101050 knockdown on proliferating and migrating CC cells, as well as the stimulating effect on apoptosis. In addition, the absence of MELK alleviated the effects of miR-140-3 p downregulation, which enhanced CC cell malignancy.CONCLUSIONSCirc_0101050 exacerbates malignant phenotypes in CC by targeting the miR-140-3 p/MELK axis. These findings suggested that the circ_0101050/miR-140-3 p/MELK network may be a prospective target for CC treatment.

2024-06-01·iScience

DDX56 promotes EMT and cancer stemness via MELK-FOXM1 axis in hepatocellular carcinoma

Article

作者: Wang, Tianyi ; Ge, XinYu ; Li, Qing ; Wang, Ximin ; Wang, Wei ; Yang, Tao

Hepatocellular carcinoma (HCC) is a major global cause of death, with epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like properties contributing to its metastasis. DEAD box helicase 56 (DDX56) is involved in carcinogenesis, but its role in EMT induction and stem phenotype maintenance is unclear. This study assessed the impact of DDX56 absence on HCC cell stemness and EMT. DDX56 was found to be overexpressed in HCC tissues, correlating with disease stage and prognosis. In vitro, DDX56 stimulated tumor cell proliferation, migration, invasion, EMT, and stemness. It also enhanced maternal embryonic leucine-zipper kinase (MELK)-mediated forkhead box protein M1 (FOXM1) expression, regulating cancer stemness and malignant traits. In vivo, DDX56 knockdown in tumor-bearing mice reduced tumorigenicity and lung metastasis by modulating the MELK-FOXM1 signaling pathway. Collectively, DDX56 initiates stem cell-like traits in HCC and promotes EMT via MELK-FOXM1 activation, shedding light on HCC pathogenesis and suggesting a potential anti-cancer therapeutic target.