IKKβ-IN-7

IKKβ-IN-7 is an IKKβ inhibitor with an IC50 value of 9.44 μM. It induces DNA damage, S-phase cell cycle arrest, ROS accumulation, loss of mitochondrial membrane potential, and apoptosis (apoptosis). IKKβ-IN-7 inhibits the phosphorylation of p65 and IκBα, blocks nuclear translocation of p65, and modulates NF-κB-regulated genes. It suppresses tumor growth in xenograft models, shows activity against colorectal cancer, and exhibits low cytotoxicity to normal cells. IKKβ-IN-7 is applicable in colorectal cancer research.

IKKβ:9.44 μM

IKKβ-IN-7 (6i2) is a potent inhibitor of the proliferation of various cancer cell lines, including A549 (IC 50 = 5.11 μM), HepG2 (IC 50 = 9.81 μM), HCT-116 (IC 50 = 1.08 μM), HT-29 (IC 50 = 4.17 μM), RKO (IC 50 = 4.72 μM), and CT-26 (IC 50 = 0.86 μM). It exhibits low cytotoxicity against normal immortalized human liver epithelial cells, THLE-2 (IC 50 > 16 μM). Upon administration for 1 hour, IKKβ-IN-7 directly inhibits IKKβ kinase activity with an IC 50 of 9.44 μM. At a concentration of 2.0 μM for 30 minutes, it significantly inhibits Topo I activity with an inhibition rate of 96.84% after incubation at 37°C for 30 minutes. IKKβ-IN-7, at 0.5-2.0 μM for 24 hours, induces various biological effects on HCT-116 cells in a dose-dependent manner: it induces DNA damage by increasing γ-H2AX expression and decreases Topo I protein levels, most effectively at 2.0 μM; it suppresses the phosphorylation of IκBα and p65, thereby inhibiting NF-κB pathway activation; it inhibits p65 nuclear translocation without altering total p65 protein levels; it regulates the expression of Bcl-2 family proteins by increasing pro-apoptotic Bax and decreasing anti-apoptotic Bcl-2, Bcl-xl, and Mcl-1, indicating induction of mitochondria-mediated apoptosis. Apoptosis is induced at 2.0 μM with an apoptosis rate of 68.29%. The compound leads to S phase cell cycle arrest at 2.0 μM; increases intracellular ROS levels; and reduces mitochondrial membrane potential. Additionally, IKKβ-IN-7 at a concentration of 0.5-2.0 μM for 24 to 48 hours inhibits wound healing migration of human colorectal cancer HCT-116 cells in a dose-dependent manner.

IKKβ-IN-7 (6i2) (2.5-60 mg/kg; intraperitoneal injection; administered once every two days for a total of two doses) demonstrates significant in vivo anti-tumor activity with good safety profile and low acute toxicity in the CT-26 xenograft model. Additionally, it exhibits favorable plasma stability and the ability to continually release SN-38.