Delving into the Latest Updates on ACT-001(Accendatech) with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

dimethylaminomicheliolide Fumarate

Target

LY96 x TLR4

Action

inhibitors, antagonists

Mechanism

LY96 inhibitors(lymphocyte antigen 96 inhibitors), TLR4 antagonists(Toll like receptor 4 antagonists)

Therapeutic Areas

NeoplasmsNervous System DiseasesRespiratory Diseases+ [6]

Active Indication

High grade gliomaDiffuse Intrinsic Pontine GliomaNon-Small Cell Lung Cancer+ [11]

Inactive Indication

EpendymomaRecurrent Glioblastoma

Originator Organization

Accendatech Co. Ltd.

Active Organization

Accendatech Co. Ltd.Tianjin Xinyi Shangde Biomedical Technology Co., Ltd.Accendatech AU Pty Ltd.

+ [1]

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationSpecial Review Project (China), Rare Pediatric Disease (United States), Orphan Drug (European Union), Fast Track (United States), Breakthrough Therapy (China)

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Structure/Sequence

Molecular FormulaC21H31NO7

InChIKeyPDWGVXJIDIRQME-DCNFBYMVSA-N

CAS Registry1582289-91-5

View All Structures (2)

主要目的：评估ACT001联合放疗治疗初诊DIPG受试者的肿瘤缓解情况和安全性（疗效探索期）、验证ACT001联合放疗对初诊DIPG受试者的肿瘤缓解情况和总生存时间的影响（疗效验证期）；次要目的：初诊DIPG受试者对ACT001联合放疗的疗效（疗效探索期）、验证ACT001联合放疗对初诊DIPG受试者的其他疗效验证ACT001联合放疗对初诊DIPG受试者的安全性（疗效验证期）；探索性目的：评估治疗对生物标志物的影响及其与疗效之间的关系、基于PopPK分析方法，表征ACT001及代谢产物的PK特征、探索ACT001的暴露与效应之间的关系

[Translation]

Primary objectives: To evaluate the tumor remission and safety of ACT001 combined with radiotherapy in newly diagnosed DIPG subjects (efficacy exploration phase), and to verify the effect of ACT001 combined with radiotherapy on tumor remission and overall survival time in newly diagnosed DIPG subjects (efficacy verification phase); Secondary objectives: To evaluate the efficacy of ACT001 combined with radiotherapy in newly diagnosed DIPG subjects (efficacy exploration phase), to verify other efficacy of ACT001 combined with radiotherapy in newly diagnosed DIPG subjects, and to verify the safety of ACT001 combined with radiotherapy in newly diagnosed DIPG subjects (efficacy verification phase); Exploratory objectives: To evaluate the impact of treatment on biomarkers and its relationship with efficacy, to characterize the PK characteristics of ACT001 and metabolites based on PopPK analysis methods, and to explore the relationship between exposure and effect of ACT001

Start Date30 Aug 2023

Sponsor / Collaborator

Tianjin Xinyi Shangde Biomedical Technology Co., Ltd.

ChiCTR2300074598

/ SuspendedPhase 2IIT

A single arm, multicenter evaluation of the safety and efficacy of ACT001 combined with radiotherapy in the newly diagnosed diffuse intrinsic pontine gliomas Phase II Clinical Study

Start Date15 Aug 2023

Sponsor / Collaborator-

100 Clinical Results associated with ACT-001(Accendatech)

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100 Translational Medicine associated with ACT-001(Accendatech)

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100 Patents (Medical) associated with ACT-001(Accendatech)

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55

Literatures (Medical) associated with ACT-001(Accendatech)

01 Mar 2025·Biochemical Pharmacology

The natural product micheliolide promotes the nuclear translocation of GAPDH via binding to Cys247 and induces glioblastoma cell death in combination with temozolomide

Article

Author: Li, Jing ; Chen, Sheng-Hua ; Wang, Ji-Yan ; Liu, Ju ; Guo, Jian-Shuang ; Liu, Ning ; Feng, Xue-Quan ; Shan, Chang-Liang ; Chen, Yue ; Bai, Gui-Ying ; Lv, Ke ; Liu, Zi-Xiao ; Deng, Yang-Ping ; Gao, Qian-Yu

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is significantly upregulated in glioblastoma (GBM) and plays a crucial role in cell apoptosis and drug resistance. Micheliolide (MCL) is a natural product with a variety of antitumour activities, and the fumarate salt form of dimethylamino MCL (DMAMCL; commercial name ACT001) has been tested in clinical trials for recurrent GBM; this compound suppresses the proliferation of GBM cells by rewiring aerobic glycolysis. Herein, we demonstrated that MCL directly targets GAPDH through covalent binding to the cysteine 247 (Cys247) residue. Intriguingly, MCL does not affect the enzyme activity of GAPDH but facilitates the nuclear translocation of the GAPDH/Siah1 (E3 ligase) complex. Furthermore, MCL/DMAMCL can exacerbate temozolomide (TMZ)-induced DNA damage. This treatment synergistically induced GBM cell death and suppressed tumour growth in a GBM xenograft mouse model. Collectively, our results reveal that MCL triggers non-glycolysis-related functions of GAPDH and that MCL promotes GBM cell death, especially when combined with TMZ, thus providing a novel strategy for clinical GBM treatment.

01 Mar 2025·Thoracic Cancer

ACT001 Suppresses the Malignant Progression of Small‐Cell Lung Cancer by Inhibiting Lactate Production and Promoting Anti‐Tumor Immunity

Article

Author: Ding, Xiao‐Jing ; Wang, Jing‐Ya ; Qin, Ting‐Ting ; Chen, Yue ; Wang, Wen‐Jing ; Huang, Ding‐Zhi ; Mei, Ting ; Lu, Ya‐Xin ; Xi, Xiao‐Nan

ABSTRACTBackgroundImproving the “cold” tumor immune microenvironment (TIME) of small‐cell lung cancer (SCLC) represents a promising therapeutic approach. The metabolite lactate plays a crucial role in shaping the immune‐cold tumor microenvironment (TME) and facilitating tumor progression. Phosphoglycerate kinase 1 (PGK1) is a key enzyme involved in tumor lactate metabolism. This study demonstrates that ACT001 improves the TIME of SCLC through inhibiting lactate production by targeting PGK1.MethodsThe cytotoxic effects of ACT001 on SCLC cell lines NCI‐H1688 and NCI‐H446 were evaluated using MTT assay, clone formation, EdU incorporation, wound healing, and invasion assays. To elucidate the mechanism of action of ACT001, proteomic techniques, pull‐down assays, LC–MS/MS, surface plasmon resonance, immunofluorescence, lactate generation, glucose uptake, and western blot assays were conducted. A xenograft model was used to assess the in vivo anti‐tumor activity of ACT001.ResultsACT001 inhibited the proliferation, invasion, and metastasis of SCLC both in vitro and in vivo. Additionally, it reduced lactate accumulation and M2 macrophage polarization. Mechanistically, ACT001 released micheliolide, which covalently modified Cys316 of PGK1 under physiological conditions. This suppressed PGK1 activity and restored the distribution of PGK1 in mitochondria and the cytoplasm under hypoxic conditions.ConclusionsACT001 inhibits the malignant progression of SCLC by suppressing lactate production, modulating macrophage polarization, and restraining tumor metastasis through PGK1 targeting.

09 Jan 2025·Journal of Medicinal Chemistry

Discovery of N-Trifluoromethylated Noscapines as Novel and Potent Agents for the Treatment of Glioblastoma

Article

Author: Cui, Guangwei ; Zhang, Yongqiang ; Wang, Pan ; Fan, Yuhang ; Zhu, Yuxin ; Deng, Haiyang ; Yang, Yue ; Wei, Jinlian ; Li, Jian ; Ma, Yiwen

The search for new and effective chemotherapeutic agents for the treatment of glioblastoma (GBM) represents an unmet need in drug discovery. Herein, a class of novel N-trifluoromethylated noscapines has been disclosed. Among them, 9'-bromo-N-trifluoromethyl noscapine 15c displayed superior in vitro anti-GBM potency. Unexpectedly, in contrast with the general N-trifluoromethyl amines, these compounds exhibited good hydrolytic stability and further investigation of this distinct stability revealed a novel strategy for the structure modification of tetrahydroisoquinoline alkaloids, where N-methyl could be bioisosterically replaced with trifluoromethyl. Furthermore, 15c showed excellent BBB permeability and good in vivo anti-GBM activity and could efficiently suppress the migration of GBM cells, while no apparent toxicity was observed, thus representing an attractive lead for further drug discovery. Further mechanistic studies revealed that 15c exhibited an ability to induce G2/M-phase arrest in GBM cells associated with the disruption of tubulin polymerization, which is consistent with the mechanism of action of noscapine.

100 Deals associated with ACT-001(Accendatech)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Small Cell Lung Cancer	Phase 2	China	Tianjin Xinyi Shangde Biomedical Technology Co., Ltd.	05 Apr 2023
Breast Cancer	Phase 2	China	Tianjin Xinyi Shangde Biomedical Technology Co., Ltd.	16 Feb 2021
Hepatocellular Carcinoma	Phase 2	China	Tianjin Xinyi Shangde Biomedical Technology Co., Ltd.	16 Feb 2021
Melanoma	Phase 2	China	Tianjin Xinyi Shangde Biomedical Technology Co., Ltd.	16 Feb 2021
Advanced Malignant Solid Neoplasm	Phase 2	China	Tianjin Xinyi Shangde Biomedical Technology Co., Ltd.	10 Sep 2020
Brain Cancer	Phase 2	China	Tianjin Xinyi Shangde Biomedical Technology Co., Ltd.	10 Sep 2020
Progressive fibrotic interstitial lung disease	Phase 2	Australia	Accendatech AU Pty Ltd.	29 Jul 2020
Glioblastoma	Phase 2	China	Accendatech Co. Ltd.	30 Jun 2020
Neuromyelitis Optica	Phase 2	China	Accendatech Co. Ltd.	14 May 2020
Recurrent Glioblastoma	Preclinical	United States	Accendatech Co. Ltd.	22 Sep 2021

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ACT001 (EHA2024)	Not Applicable	Primary Central Nervous System Lymphoma	-	ACT001	sqbmgzktwz(gzsyngnuvn) = iyapznxkls pvvffgzwcd (yfmcsjrusx )	Positive	14 May 2024