ACT001 is an Orally Active PAI-1 Inhibitor

Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumour in adults, with a high morbidity, high mortality and poor patient prognosis. Platinum-based drugs, including cisplatin, are commonly used in tumor therapy. Cisplatin served as a neoadjuvant therapy with temozolomide and as an adjuvant therapy with carmustine in malignant glioma therapy. However, drug resistance and serious side effects are some of the inadequacies of platinum-based drugs for the treatment of GBM. The treatment of glioma urgently needs the development of new therapeutic drugs or establishment of new combination therapies to improve patient survival and reduce the side effects of conventional chemotherapy.

ACT001 serves as a promising drug for the treatment of GBM and it was designated as an orphan drug for GBM by the FDA. The compound is derived from the structural modification of parthenolide (PTL), a well-studied anti-inflammatory and anticancer agent. However, PTL is unstable in both acidic and basic conditions, limiting its clinical application. Micheliolide (MCL) has the same anticancer structure as PTL but has more persistent stability in the plasma than PTL9. DMAMCL is the dimethylamino Michael adduct of MCL, and ACT001 is the fumarate salt form of DMAMCL.

ACT001 is an Orally Active PAI-1 Inhibitor.

ACT001/DMAMCL have shown potent anticancer and anti-inflammatory activity. PTL has been shown to significantly inhibit the activity of the NFκB and STAT3 pathways, which are important pathways in both inflammation and cancer. However, how ACT001 regulates the anti-GBM immune response has not been elucidated.

PD-L1 mRNA expression significantly associates with immunosuppression and predicts very poor survival in patients. Chemoradiation increases PD-L1 expression. Temozolomide (TMZ)-challenged GBM cells strongly suppress pro inflammatory activity via enhanced transcription of PD-L1 but no other immune checkpoints, such as CD276, HVEM or galectin-925.

Firstly, in vitro, ACT001 (0-1000 μM; 24-96 hours) decreases cell viability when the concentration was higher than 10 μM in SNB19, U251MG cell lines. Moreover, ACT001 (10 μM; 48 h) can induce apoptosis in U118MG cells. ACT001 (3.75, 7.5 μM; 48 h) combined with Cisplatin (1-100 μM) increases the apoptosis of U118MG cells over either drug alone.

Secondly, ACT001 (20-80 μM) decreases the expression of PD-L1 and phosphorylation of STAT3 in a dose-dependent manner.

Also, in vivo, ACT001 (10-40 μM) significantly decreases PD-L1 expression in a dose-dependent manner. And it (10 μM) inhibits the migration, invasion and vascular formation ability of U118MG cells.


Luqing Tong, et al. ACT001 reduces the expression of PD-L1 by inhibiting the phosphorylation of STAT3 in glioblastoma. Theranostics. 2020 May 1;10(13):5943-5956.

Xiaonan Xi, et al. ACT001, a novel PAI-1 inhibitor, exerts synergistic effects in combination with cisplatin by inhibiting PI3K/AKT pathway in glioma. Cell Death Dis. 2019 Oct 7;10(10):757.