PARP1/c-Met-IN-1 (Compound 16) serves as a selective dual inhibitor targeting both PARP1 and c-Met, demonstrating IC50 values of 3.3 nM and 32.2 nM, respectively. This compound effectively induces apoptosis and causes cell cycle arrest at the G2/M phase in MDA-MB-231 cells. Furthermore, PARP1/c-Met-IN-1 displays notable antitumor activity in mouse models [1].

PARP1:3.3 nM, c-Met:32.2 nM

PARP1/c-Met-IN-1 at a concentration of 1 μM enhances the thermal stability of PARP1 and c-Met, and inhibits the expression of associated proteins PAR, p-c-Met, and p-AKT, thereby affecting the interaction between PARP1 and c-Met, which leads to DNA damage [1]. In the concentration range of 0.5-1 μM, it reduces homologous recombination (HR) function in MDA-MB-231 cells by downregulating BRCA1 and Rad51 expression [1]. According to Western Blot analysis on MDA-MB-231 cells incubated for 72 hours at 1 μM, the compound increased protein stability in the temperature range of 43–55 °C and decreased BRCA1 and Rad51 expressions [1].

In a study involving BALB/c nude mice with xenografts of MDA-MB-231 and HCT116OR tumors, the chemical compound PARP1/c-Met-IN-1 administered intraperitoneally at doses of 12.5-100 mg/kg for 28 days demonstrated tumor growth inhibition rates of 49-77% for MDA-MB-231 and 62-70% for HCT116OR tumors [1]. Pharmacokinetic analysis in BALB/c mice revealed that PARP1/c-Met-IN-1 exhibited a half-life of 1.42 hours at a 10 mg/kg dose, with peak plasma concentration (T max) at 0.25 hours and a maximum concentration (C max) of 152.47 ng/mL. The area under the curve (AUC 0-t) was 95.42 ng·h/mL and AUC 0-inf was 96.70 ng·h/mL, while the mean residence time (MRT 0-t) was 1.67 hours and MRT 0-inf was 1.77 hours. The clearance rate was calculated at 121232 mL/h/kg. For these animal models, the MDA-MB-231 and HCT116OR xenografts in BALB/c nude mice received varying dosages, with MDA-MB-231 xenograft mice treated with 12.5-50 mg/kg and HCT116OR xenograft mice with 20-100 mg/kg over 21 and 28 days respectively. These treatments resulted in tumor growth inhibition (TGI) of 49-77% in MDA-MB-231 and 62-70% in HCT116OR xenograft mice.