HJ03

HJ03 is an orally bioavailable inducer of DNA damage and ferroptosis (ferroptosis) that can cross the blood-brain barrier. It triggers ferroptosis by enhancing intracellular ROS, Fe2+ accumulation, and lipid peroxidation. HJ03 induces DNA adducts and interstrand crosslinks, hindering DNA replication and transcription, leading to G2/M phase arrest and cell apoptosis (apoptosis). It is applicable for research on glioblastoma multiforme and colorectal cancer.

HJ03 (24-72 h) effectively inhibits the viability of U251, U87, T98G, HCT116, MSH6-deficient U251, and MSH6-deficient T98G cells, with IC50 values ranging from 0.8914 μM to 61.65 μM under 24, 48, and 72 h incubation, independent of MGMT and MSH6 status. At 0.25-8 μM over 14 days, HJ03 causes dose-dependent inhibition of colony formation in U251, U87, and T98G cells. When administered at 4-16 μM for 72 h, it suppresses U87 spheroid viability and induces cell death, with 16 μM leading to near-complete spheroid death. HJ03 (1-5 μM; 48-72 h) induces G2/M phase arrest in U251 and U87 cells and modulates cell cycle-related proteins (p21, p-CDK1, CDK1, cyclin B1) in U251, U87, and T98G cells. At 1-40 μM for 48-72 h, it induces apoptosis in U251, U87, and T98G cells via dose-dependent cleavage of caspase-3/7/9 and PARP. HJ03 (1-80 μM; 48-72 h) also triggers ferroptosis in these cells by upregulating ROS, Fe2+, and MDA levels, downregulating SLC7A11, and upregulating p53 or ATF3. Furthermore, at 0.4-50 μM for 15-72 h, HJ03 induces DNA damage in U251, U87, and T98G cells by activating the ATM-Chk2 DNA damage response pathway and causes dose-dependent DNA cross-linking and alkylation in linearized pBR322 DNA.

HJ03, when administered orally at doses of 2-20 mg/kg for 5 consecutive days per week over a period of 4 weeks, significantly prolongs the survival of mice implanted with glioblastoma. Additionally, HJ03, given at doses ranging from 2-132 mg/kg once daily for 7 consecutive days, is well-tolerated in healthy mice at doses up to 66 mg/kg, with no notable weight loss or hematological toxicity observed. However, a dose of 132 mg/kg induces mild hematological toxicity.