VS-5584(VS-5584) - 药物靶点：PI3K family x mTORC1 x mTORC2_专利_临床

概要

基本信息

药物类型

小分子化药

别名

+ [1]

靶点

PI3K family x mTORC1 x mTORC2

作用机制

Phosphatidylinositol 3-kinase family inhibitors、mTORC1抑制剂(哺乳动物雷帕霉素靶蛋白(mTORC1)复合体抑制剂)、mTORC2抑制剂(mTOR复合物-2抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病+ [1]

在研适应症-

非在研适应症

晚期恶性实体瘤淋巴瘤间皮瘤+ [2]

原研机构

杏国新药股份有限公司

在研机构-

非在研机构

Strike Bio, Inc.

Verastem, Inc.

最高研发阶段终止临床1期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C17H22N8O

InChIKeyQYBGBLQCOOISAR-UHFFFAOYSA-N

CAS号1246560-33-7

关联

2

项与 VS-5584 相关的临床试验

NCT02372227 / Terminated临床1期

A Phase 1 Dose Escalation Study of VS-5584, a Dual PI3K/mTOR Inhibitor, Administered With a Fixed Dose of VS-6063, a Focal Adhesion Kinase Inhibitor, in Subjects With Relapsed Malignant Mesothelioma

The purpose of this study is to evaluate rising dose levels of VS-5584 administered in combination with a fixed dose of VS-6063 in subjects with relapsed malignant mesothelioma to determine a recommended Phase 2 dose (RP2D) for further development of this combination in this indication.

开始日期2015-01-01

申办/合作机构

Verastem, Inc.

NCT01991938 / Terminated临床1期

A Phase I Dose Escalation Study of VS-5584, a Dual PI3K/mTOR Inhibitor, in Subjects With Advanced Non-Hematologic Malignancies or Lymphoma

This is a Phase I, open-label, multicenter, dose-escalation trial of VS-5584, a PI3K/mTOR kinase inhibitor, in subjects with advanced non-hematologic malignancies or lymphoma. This clinical study is comprised of 2 sequential parts: Part 1 (Dose Escalation) and Part 2 (Expansion). The purpose of this study is to evaluate the safety (including the recommended Phase II dose), pharmacokinetics (the amount of VS-5584 in subject's blood) and the anti-cancer activity of VS-5584. Biomarkers (genes or proteins that may predict or show how subject's body may respond to VS-5584) will also be assessed in archival tumor tissue, tumor biopsies (in consenting subjects), and blood samples.

开始日期2013-11-01

申办/合作机构

Verastem, Inc.

100 项与 VS-5584 相关的临床结果

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100 项与 VS-5584 相关的转化医学

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100 项与 VS-5584 相关的专利（医药）

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24

项与 VS-5584 相关的文献（医药）

2024-02-01·Nucleosides, Nucleotides & Nucleic Acids

The lncRNA expression profile signature of leukemia stem cells is altered upon PI3K/mTOR inhibition: an in vitro and in silico study

Article

作者: Kayabasi, Cagla ; Gunduz, Cumhur

Genetic and/or epigenetic alterations in hematopoietic stem cells (HSCs) contribute to leukemia stem cell (LSC) formation. We aimed to identify alterations in the lncRNA expression profile signature of LSCs upon inhibition of PI3K/Akt/mTOR signaling, which provides selective advantages to LSCs. We also aimed to elucidate the potential interaction networks and functions of differentially expressed lncRNAs (DELs). We suppressed PI3K/Akt/mTOR signaling in LSC and HSC cell-lines by specific PI3K/mTOR dual-inhibitor (VS-5584) and confirmed the inhibition by antibody-array. We defined DELs by qRT-PCR. Increased SRA, ZEB2-AS1, antiPeg11, DLX6-AS, SNHG4, and decreased H19, PCGEM1, CAR-Intergenic-10, L1PA16, IGF2AS, and SNHG5 levels (|log2fold-change|>5) were strictly associated with PI3K/Akt/mTOR pathway inhibition in LSC. We performed in silico analyses for DELs. ZEB2-AS1 was found to be specifically expressed in normal bone marrow and predominantly lower in leukemic cell-lines. Three sub-clusters were identified for DELs and they were associated with "abnormality of multiple cell lineages in the bone marrow." DELs were most highly enriched for "glucuronidation" Reactome pathway and "ascorbate and aldarate metabolism" and "inositol phosphate metabolism" KEGG pathways. Transcription factors, MBD4, NANOG, PAX6, RELA, CEBPB, and CEBPA were predicted to be associated with the DEL profile. SRA was predicted to interact with CREB1, RARA, and PPARA. The possible DELs' targets were predicted to form six ontological groups, be highly enriched for phosphoprotein, and be involved in "PPAR signaling pathway" and "ChREBP regulation by carbohydrates and cAMP." These results will help to elucidate the roles of lncRNAs in the mechanisms that provide selective advantages to leukemia stem cells.

2023-10-01·European Journal of Pharmacology

PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer

Article

作者: Li, Junbiao ; Jiang, Jie ; Wang, Rong ; Li, Fei ; Li, Gang ; Li, Yibin ; Zhao, Senxia ; Mi, Yanjun ; Ye, Juanping ; Zhang, Xiaoting ; Gao, Chang

Small molecule drugs are of significant importance in the treatment of non-small cell lung cancer (NSCLC). Here, we explored biological effects of the PI3K/mTOR inhibitor VS-5584 on NSCLC. Our findings indicated that VS-5584 administration resulted in a dose-dependent inhibition of NSCLC cell proliferation, as well as the induction of apoptosis and cycle arrest. Additionally, we observed a significant increase in intracellular reactive oxygen species (ROS) levels following VS-5584 treatment. The use of the ROS inhibitor N-acetylcysteine (NAC) effectively reduced ROS levels and decreased the proportion of apoptotic cells. Treatment with VS-5584 led to an upregulation of genes associated with apoptosis and cell cycle, such as c-caspase 3 and P21. Conversely, a downregulation of cyclin-dependent kinase 1 (CDK1) expression was observed. Next, transcriptome analyses revealed that VS-5584 treatment altered the abundance of 1520 genes/transcripts in PC-9 cells, one of which was polo-like kinase 1 (PLK1). These differentially expressed genes were primarily enriched in biological processes such as cell cycle regulation and cell apoptosis, which are closely linked to the P53 and apoptosis pathways. Co-treatment with VS-5584 and PLK1 inhibitor NMS-P937 resulted in enhanced cancer cell death, exhibiting synergistic inhibitory activity. Notably, VS-5584 inhibited the growth of NSCLC in a patient-derived xenograft (PDX) mouse model without observable abnormalities in major organs. Overall, VS-5584 effectively suppressed the growth of NSCLC cells both in vitro and in vivo. VS-5584 combined with NMS-P937 exhibited a synergistic effect in inhibiting NSCLC cell growth. These findings suggest that VS-5584 has potential as a therapeutic strategy for treating NSCLC.

2023-09-01·Cancer Medicine

SIRT2 inhibitor SirReal2 enhances anti‐tumor effects of PI3K/mTOR inhibitor VS‐5584 on acute myeloid leukemia cells

Article

作者: Xia, Junjie ; Zha, Jie ; Jian, Xinyi ; Zhu, Jingtao ; Zhang, Liyi ; Luo, Yiming ; Zhang, Li ; Zhao, Haijun ; Qi, Zhongquan ; Xu, Bing ; Ding, Yi

AbstractBackgroundAcute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML.MethodsThe up‐regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used.ResultsThrough bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small‐molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS‐5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS‐5584 induced apoptosis and cycle arrest of AML cells in a dose‐ and time‐dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS‐5584 treatment, with 287 proteins being down‐regulated and 71 proteins being up‐regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS‐5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS‐5584 caused a significant reduction in the half‐maximal inhibitory concentration (IC50) of VS‐5584 on AML cells. In vivo, experiments suggested that VS‐5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein.ConclusionsTaken together, the PI3K/mTOR inhibitor VS‐5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

100 项与 VS-5584 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12986

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
恶性间皮瘤	临床1期	英国	Verastem, Inc.	2015-01-01
恶性间皮瘤	临床1期	美国	Verastem, Inc.	2015-01-01
晚期恶性实体瘤	临床1期	美国	Verastem, Inc.	2013-11-01
晚期恶性实体瘤	临床1期	英国	Verastem, Inc.	2013-11-01
肿瘤转移	临床1期	美国	Verastem, Inc.	2013-11-01
肿瘤转移	临床1期	英国	Verastem, Inc.	2013-11-01
淋巴瘤	临床1期	-	Strike Bio, Inc.	-
淋巴瘤	临床1期	-	Strike Bio, Inc.	-
间皮瘤	临床1期	-	Strike Bio, Inc.	-