TOP1/TDP1-IN-1

TOP1/TDP1-IN-1 is an inhibitor of DNA topoisomerase 1B (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) with a TDP1 IC50 of 17.8 μM. It directly inhibits the catalytic activity of TOP1 without forming a DNA-TOP1 ternary complex. This compound disrupts TDP1-mediated TOP1-induced DNA damage repair, exhibits low acute toxicity, and interferes with DNA repair pathways. It induces apoptosis, inhibits clonogenic capacity, and produces antiproliferative effects in cancer cells. TOP1/TDP1-IN-1 can be utilized in research on non-small cell lung cancer, cervical cancer, and colon cancer.

TDP1:17.8 μM

TOP1/TDP1-IN-1 (C13) at concentrations ranging from 6.25 to 100 μM significantly inhibits the enzyme activity of calf thymus TOP1 in a concentration-dependent manner, surpassing the potency of 50 μM CPT. When incubated for 30 minutes, TOP1/TDP1-IN-1 inhibits purified TDP1 enzyme activity with an IC50 value of 17.8 μM. Furthermore, after 48 hours of treatment, TOP1/TDP1-IN-1 potently inhibits the proliferation of A549, HeLa, and HCT116 cancer cells with IC50 values of 0.89 μM, 1.2 μM, and 1.1 μM, respectively. Within a concentration range of 0.125-0.5 μM and following a 48-hour treatment plus a 10-day culture period, the compound effectively impairs the clonogenic survival ability of A549 cells in a concentration-dependent manner. Also, at concentrations between 0.5-2 μM, and following exposure for 12, 24, and 36 hours, it significantly suppresses A549 cell migration in a dose-responsive manner. TOP1/TDP1-IN-1 induces significant DNA damage in A549 cells at concentrations of 1 μM and 2 μM as validated by the formation of γ-H2AX foci after 3 hours of treatment. Additionally, it induces apoptosis of A549 cells in vitro in a dose-dependent fashion at concentrations of 1-4 μM over 48 hours. At 1 μM over 48 hours, it acts synergistically with Topotecan to inhibit A549 cell proliferation.

TOP1/TDP1-IN-1 (C13) administered intraperitoneally at doses of 20-80 mg/kg daily for 8 consecutive days demonstrates dose-dependent antitumor efficacy in a Lewis lung carcinoma xenograft model, with good tolerability noted at 20 mg/kg. In an acute toxicity study, a single intraperitoneal dose of TOP1/TDP1-IN-1 at 123-300 mg/kg in Kunming mice shows complete survival at doses ≤154 mg/kg, while a 100% mortality rate is observed at doses of 192 mg/kg and above. Administered as a single dose of 4 mg/kg intravenously or 20 mg/kg orally, TOP1/TDP1-IN-1 displays favorable pharmacokinetic properties in Sprague-Dawley rats, including high oral bioavailability (91.3%) and prolonged systemic exposure.