Bax activator-2

Baxactivator-2 (compound 27c) is a pro-apoptotic agent targeting BAX, with an IC50 of 0.30 μmol/L for human BAX. It binds to BAX's trigger site, inducing a conformational change. Baxactivator-2 triggers mitochondrial depolarization, cytochrome c release, and caspase-3/9 and PARP cleavage, leading to apoptosis. It exhibits cytotoxicity across various cancer cell lines, with reduced cytotoxicity in BAX-knockout A549 cells and lower toxicity to non-cancer cell lines. This compound is applicable in research on acute myeloid leukemia and solid tumors.

Bax activator-2 (compound 27c) selectively binds to recombinant human BAX with a submicromolar IC50 of 0.30 μmol/L, as demonstrated in competitive fluorescence polarization binding assays within a concentration range of 0.024-100 μmol/L. At 100 μmol/L, it induces time-dependent oligomerization of recombinant human BAX protein in vitro over 1-4 hours. Furthermore, Bax activator-2 at 40 μmol/L selectively binds to BAX, enhancing its thermal stability in BxPC-3 cells, without interacting with BAK. The compound promotes dose-dependent translocation of recombinant human BAX to mitochondrial-mimetic liposomes, with activity enhanced when combined with BIM SAHB. It also synergizes with BIM-BH3 peptide to increase the permeability of ANTS/DPX-loaded liposomes mediated by recombinant human BAX. In terms of cytotoxicity, Bax activator-2 exhibits BAX-dependent cytotoxic effects on hematological cancer cell lines with an IC50 ranging from submicromolar to low micromolar levels, while displaying lower toxicity in non-cancer cell lines. In THP-1 cells, it induces dose-dependent translocation of BAX to mitochondria and cytochrome c release within 6 hours. Additionally, at concentrations of 2-10 μmol/L for 20 hours, it causes dose-dependent apoptosis in THP-1 cells, with 62.8% of cells entering late-stage apoptosis after treatment with 10 μmol/L for 20 hours.

Bax activator-2 (compound 27c) (5-10 mg/kg; intraperitoneal injection, intravenous injection; single dose) demonstrates rapid absorption, good distribution, moderate bioavailability, relatively short half-life, and swift clearance following a single intraperitoneal or intravenous administration in healthy male ICR mice.