Delving into the Latest Updates on VS-5584 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

PI3K family x mTORC1 x mTORC2

Mechanism

Phosphatidylinositol 3-kinase family inhibitors, mTORC1 inhibitors(Mammalian target of Rapamycin (mTORC1) inhibitors), mTORC2 inhibitors(mTOR Complex 2 inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases+ [1]

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmLymphomaMesothelioma+ [2]

Originator Organization

SynCore Biotechnology Co., Ltd.

Active Organization-

Inactive Organization

Strike Bio, Inc.

Verastem, Inc.

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC17H22N8O

InChIKeyQYBGBLQCOOISAR-UHFFFAOYSA-N

CAS Registry1246560-33-7

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.

Start Date01 Nov 2013

Sponsor / Collaborator

Verastem, Inc.

100 Clinical Results associated with VS-5584

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100 Translational Medicine associated with VS-5584

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100 Patents (Medical) associated with VS-5584

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24

Literatures (Medical) associated with VS-5584

01 Feb 2024·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

Author: 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.

01 Oct 2023·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

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

01 Sep 2023·Cancer Medicine

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

Article

Author: Xia, Junjie ; Zha, Jie ; Jian, Xinyi ; Zhu, Jingtao ; Zhang, Liyi ; Zhang, Li ; Luo, Yiming ; 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 Deals associated with VS-5584

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12986

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Mesothelioma, Malignant	Phase 1	GB	Verastem, Inc.	01 Jan 2015
Mesothelioma, Malignant	Phase 1	US	Verastem, Inc.	01 Jan 2015
Advanced Malignant Solid Neoplasm	Phase 1	US	Verastem, Inc.	01 Nov 2013
Advanced Malignant Solid Neoplasm	Phase 1	GB	Verastem, Inc.	01 Nov 2013
Neoplasm Metastasis	Phase 1	US	Verastem, Inc.	01 Nov 2013
Neoplasm Metastasis	Phase 1	GB	Verastem, Inc.	01 Nov 2013
Lymphoma	Phase 1	-	Strike Bio, Inc.	-
Lymphoma	Phase 1	-	Strike Bio, Inc.	-
Mesothelioma	Phase 1	-	Strike Bio, Inc.	-