ACT-001(Accendatech)

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. Our previous work has revealed that MCL/DMAMCL could suppress 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 enzymatic 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.

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.