Definition

The fumarate salt form of the parthenolide derivative micheliolide (MCL), and an orally bioavailable guaianolide sesquiterpene lactone and inhibitor of the protease plasminogen activator inhibitor-1 (PAI-1), with potential immunomodulating and antineoplastic activities. Upon oral administration, PAI-1 inhibitor ACT001 targets and binds to PAI-1, thereby inhibiting the PAI-1/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. This induces apoptosis in and inhibits the proliferation, migration and invasion of tumor cells in which the PI3K/AKT pathway is overexpressed. In addition, ACT001 binds to and inhibits the activity of inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-beta), thereby inhibiting nuclear factor kappa B (NF-kB) signaling. This leads to the downregulation of manganese superoxide dismutase (MnSOD) and induces the generation of reactive oxygen species (ROS). This induces G2/M phase arrest and tumor cell apoptosis. Also, ACT001 binds to and inhibits the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and reduces the expression of programmed death-ligand 1 (PD-L1). This may modulate the anti-tumor immune response. ACT001 may also affect tissue remodeling and cancer metabolism. PAI-1 plays a key role in the proliferation, migration, invasion and adhesion of cancer cells as well as multidrug resistance. It is highly expressed in certain tumors, such as gliomas. ACT001 is able to cross the blood-brain barrier (BBB).