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DRUG:

dimethylamino micheliolide (ACT001)

i
Other names: ACT001, ACT 001
Associations
Trials
Company:
Tianjin Suntech Pharma
Drug class:
STAT3 inhibitor, NF-κB inhibitor, PAI-1 inhibitor, Pyruvate kinase-M2 activator
Associations
Trials
5ms
MCL restrained ROS/AKT/ASAH1 pathway to therapy tamoxifen resistance breast cancer by stabilizing NRF2. (PubMed, Cell Prolif)
In addition, ACT001, the prodrug of MCL, significantly inhibited the tumour growth of TAMR cells in preclinical xenograft tumour models. MCL could activate the cellular antioxidant system via NRF2/KEAP1 and inhibit ASAH1 expression through the ROS/AKT signalling pathway, thus suppressing cell proliferation. MCL could be used as a potential treatment for TAMR-BC.
Journal
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ER (Estrogen receptor) • KEAP1 (Kelch Like ECH Associated Protein 1)
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tamoxifen • dimethylamino micheliolide (ACT001)
8ms
Alleviative effects of the parthenolide derivative ACT001 on insulin resistance induced by sodium propionate combined with a high-fat diet and its potential mechanisms. (PubMed, Eur J Pharmacol)
In addition, the results of the running wheel experiment indicated that ACT001 alleviated the circadian rhythm disorder caused by insulin resistance to a certain extent. This study revealed the potential mechanism by which ACT001 alleviates insulin resistance and provides ideas for developing natural antidiabetic drugs.
Journal
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FABP4 (Fatty Acid Binding Protein 4)
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dimethylamino micheliolide (ACT001)
8ms
Anlotinib Inhibits Cisplatin Resistance in Non-Small-Cell Lung Cancer Cells by Inhibiting MCL-1 Expression via MET/STAT3/Akt Pathway. (PubMed, Can Respir J)
Anlotinib is an effective targeted therapy for advanced non-small-cell lung cancer (NSCLC) and has been found to mediate chemoresistance in many cancers. Furthermore, MET overexpression reversed the inhibitory effect of anlotinib on the DDP resistance of NSCLC cells, and this effect could be eliminated by MCL-1 knockdown or ACT001 (an inhibitor for STAT3/Akt pathway). Our results confirmed that anlotinib inhibited DDP resistance in NSCLC cells, which might decrease MCL-1 expression via mediating the MET/STAT3/Akt pathway.
Journal
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MCL1 (Myeloid cell leukemia 1)
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MET overexpression • MET expression • MCL1 expression • STAT3 expression
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cisplatin • Focus V (anlotinib) • dimethylamino micheliolide (ACT001)
10ms
Trial completion • Metastases
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dimethylamino micheliolide (ACT001)
12ms
ACT001 Alleviates chronic kidney injury induced by a high-fat diet in mice through the GPR43/AMPK pathway. (PubMed, Lipids Health Dis)
This study is the first to look at ACT001's potential as a treatment for obesity-related kidney disease. Regulating GPR43 and AMPK signalling pathways, By controlling the GPR43 and AMPK signalling pathways, ACT001 improves colitis and the intestinal mucosal barrier, decreases renal lipid deposition, and suppresses inflammation and oxidative stress in the kidneys. According to this study, ACT001 could be a viable ORG therapy option.
Preclinical • Journal
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NLRP3 (NLR Family Pyrin Domain Containing 3) • TJP1 (Tight Junction Protein 1) • OCLN (Occludin)
|
dimethylamino micheliolide (ACT001)
1year
A phase 2 study to evaluate efficacy and safety of ACT001 and temozolomide combination treatment in patients with recurrent glioblastoma multiforme (SNO 2023)
ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.
Clinical • P2 data
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • MGMT (6-O-methylguanine-DNA methyltransferase)
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IDH1 mutation • IDH1 R132H • IDH wild-type • IDH1 R132
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temozolomide • dimethylamino micheliolide (ACT001)
1year
Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins. (PubMed, Blood Sci)
Moreover, dimethylaminomicheliolide (DMAMCL), an orally available derivative of MCL, significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis. Mechanistically, MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation, thus inhibiting JAK/STAT signaling. Overall, these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.
Journal
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STAT3 (Signal Transducer And Activator Of Transcription 3)
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JAK2 V617F
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Jakafi (ruxolitinib) • dimethylamino micheliolide (ACT001)
1year
ACT001 alleviates inflammation and pyroptosis through the PPAR-γ/NF-κB signaling pathway in LPS-induced alveolar macrophages. (PubMed, Genes Genomics)
ACT001 significantly ameliorated inflammation and pyroptosis via the PPAR-γ/NF-κB signaling pathways in LPS-induced NR8383 alveolar macrophages.
Journal
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NLRP3 (NLR Family Pyrin Domain Containing 3) • PPARA (Peroxisome Proliferator Activated Receptor Alpha)
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dimethylamino micheliolide (ACT001)
over1year
ACT001 inhibited CD133 transcription by targeting and inducing Olig2 ubiquitination degradation. (PubMed, Oncogenesis)
Furthermore, we verified ACT001, a guaianolide sesquiterpene lactone in phase II clinical trial with excellent glioma remission, inhibited cancer stemness by directly binding to Olig2 protein, inducing Olig2 ubiquitination degradation and inhibiting CD133 gene transcription. All these results suggested that Olig2 could be an excellent druggable target in anti-LCSCs therapy and lay a foundation for the further application of ACT001 in the treatment of lung cancer in clinical.
Journal
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OLIG2 (Oligodendrocyte Transcription Factor 2)
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dimethylamino micheliolide (ACT001)
almost2years
Journal
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BCL2L11 (BCL2 Like 11)
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dimethylamino micheliolide (ACT001)
over2years
ACT001 Inhibits TLR4 Signaling by Targeting Co-Receptor MD2 and Attenuates Neuropathic Pain. (PubMed, Front Immunol)
Furthermore, systemic administration of ACT001 attenuated allodynia induced by peripheral nerve injury and activation of microglia and astrocyte in vivo. Given the well-established role of neuroinflammation in neuropathic pain, these data imply that ACT001 could be a potential drug candidate for the treatment of chronic neuropathic pain.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IL6 (Interleukin 6) • TNFA (Tumor Necrosis Factor-Alpha) • IL1B (Interleukin 1, beta)
|
dimethylamino micheliolide (ACT001)
almost3years
ACT001 inhibits pituitary tumor growth by inducing autophagic cell death via MEK4/MAPK pathway. (PubMed, Acta Pharmacol Sin)
Specifically, ACT001 treatment promoted the phosphorylation of JNK and P38 by binding to mitogen-activated protein kinase kinase 4 (MEK4). Our study indicated that ACT001-induced ACD of pituitary tumor cells via activating JNK and P38 phosphorylation by binding with MEK4, and it might be a novel and effective anticancer drug for pituitary adenomas.
Journal
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ATG7 (Autophagy Related 7) • MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4)
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dimethylamino micheliolide (ACT001)
almost4years
Targeting of glioma stem-like cells with a parthenolide derivative ACT001 through inhibition of AEBP1/PI3K/AKT signaling. (PubMed, Theranostics)
ACT001 exhibits antitumor activity either as a single agent or in combination with SHP099, which provides significant survival benefits for GSC tumor xenograft-bearing animals. Our data demonstrate AEBP1 as a new druggable target in GBM and ACT001 as a potential therapeutic option for improving the clinical treatment of GBM in combination with SHP099.
Journal
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AEBP1 (AE Binding Protein 1)
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SHP099 • dimethylamino micheliolide (ACT001)
over4years
Anticancer Effects of ACT001 via NF-κB Suppression in Murine Triple-Negative Breast Cancer Cell Line 4T1. (PubMed, Cancer Manag Res)
ACT001 is a novel sesquiterpene lactone derivative with anticancer effects, including the reversal of tamoxifen resistance in estrogen receptor-positive breast cancer cells. Our results suggest that ACT001 exerts its anticancer effects by inducing apoptosis in murine TNBC cell line 4T1 and regulates the tumor microenvironment by attenuating angiogenesis and accumulation of MDSCs in 4T1 tumors. The underlying mechanism may involve the suppression of NF-κB activity.
Preclinical • Journal
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ER (Estrogen receptor) • CSF2 (Colony stimulating factor 2)
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ER positive
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tamoxifen • dimethylamino micheliolide (ACT001)
over4years
ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma. (PubMed, Theranostics)
ACT001 inhibits PD-L1 transcription and modulates anti-tumor immune response in glioma bearing mice. These findings will help us to understand the mechanism of ACT001 in GBM therapy.
Journal • PD(L)-1 Biomarker
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STAT3 (Signal Transducer And Activator Of Transcription 3) • CD163 (CD163 Molecule)
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PD-L1 expression
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dimethylamino micheliolide (ACT001)
almost5years
ACT001 modulates the NF-κB/MnSOD/ROS axis by targeting IKKβ to inhibit glioblastoma cell growth. (PubMed, J Mol Med (Berl))
The inhibition of p-IKKβ induced the generation of ROS. ACT001 promoted the generation of ROS by regulating MnSOD expression to induce G/M phase arrest.
Journal
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BAX (BCL2-associated X protein) • CDK1 (Cyclin-dependent kinase 1) • CCNB1 (Cyclin B1)
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dimethylamino micheliolide (ACT001)