Background:
ACT001 is an orally active PAI-1 inhibitor by inhibiting the phosphorylation of PI3K and AKT. ACT001 inhibits the phosphorylation of STAT3 and PD-L1 expression by directly binding to STAT3. ACT001, a fumarate salt form of DMAMCL (a prodrug of Micheliolide), can cross the blood-brain barrier. ACT001 has potent anti-glioblastoma (GBM) activity and immunomodulatory effects[1][2].
ACT001 (0-1000 μM; 24-96 hours) decreases cell viability when the concentration was higher than 10 μM in SNB19, U251MG cell lines[1]. 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[2]. ACT001 (20-80 μM) decreases the expression of PD-L1 and phosphorylation of STAT3 in a dose-dependent manner[1]. ACT001 (10-40 μM) significantly decreases PD-L1 expression in a dose-dependent manner[1]. ACT001 (10 μM) inhibits the migration, invasion and vascular formation ability of U118MG cells[2].
ACT001 (100 or 400 mg/kg/day; Orally; starting on day 7 for 42 days) significantly causes survived longer than control mice and decreases p-STAT3 and PD-L1 expression with 400 mg/kg[1]. ACT001 (200 mg/kg/day; oral administration) enhances the antitumour effect of Cisplatin (2.5 mg/kg, once every 3 days, IP) in U118 xenograft model[2].
[1]. 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.
[2]. 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.
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