ATM-IN-13

ATM-IN-13 (A36) is an orally active selective ATM kinase inhibitor with a human IC50 of 0.3 nM. It disrupts the ATM-mediated DNA double-strand break repair signaling pathway, reduces phosphorylation levels of ATM and p53, and inhibits the ATM-dependent DNA damage response. ATM-IN-13 is applicable in colorectal cancer research.

ATM-IN-13 (A36) is a potent inhibitor of purified ATM kinase, with an IC50 of 0.3 nM. It demonstrates high kinase selectivity, showing over 3333-fold selectivity for ATR, mTOR, and PI3Kα and 493-fold selectivity for DNA-PK compared to its ATM IC50. ATM-IN-13 (A36) inhibits the proliferation of HCT116 colorectal cancer cells exposed to 2 Gy irradiation with an IC50 of 1.7 nM. At concentrations of 20-40 nM over 6 days, it significantly enhances the cytotoxicity of irinotecan in HCT116 and SW620 colorectal cancer cells, showing greater synergy in SW620. With 10-20 nM, ATM-IN-13 (A36) enhances irinotecan's inhibition of colorectal cancer cell colony formation. At 2 μM, it inhibits the activation of ATM signaling by irinotecan in HCT116 cells, reducing levels of γ-H2AX, phosphorylated ATM, and phosphorylated p53. At concentrations of 0.5-2 μM, it decreases γ-H2AX levels induced by irinotecan in HCT116 cells in a dose-dependent manner, confirming its inhibition of ATM-mediated DNA damage signaling. Alone, ATM-IN-13 (A36) at 0.008-1 μM for 48 hours does not alter the cell cycle distribution of HCT116 or SW620 cells, but enhances irinotecan-induced G2/M phase arrest in a concentration-dependent manner. At 0.25-0.5 μM for 48 hours, it does not induce apoptosis in HCT116 cells by itself but enhances irinotecan-induced apoptosis in a concentration-dependent manner. It exhibits good metabolic stability in human and rat liver microsomes and mouse/rat plasma, though stability in mouse liver microsomes is poor. Its solubility at 25°C (pH 7) is excellent at 1258.1 μg/mL. ATM-IN-13 (A36) has a low potential for drug-drug interactions, with IC50 values greater than 30 μM for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 inhibition.

ATM-IN-13 (A36) administered at doses of 20-40 mg/kg via oral gavage once daily for 12 days, in combination with liposomal irinotecan, achieved tumor growth inhibition rates of 82.3% and 92.6% in an HCT116 colorectal cancer xenograft model, demonstrating good safety. Similarly, ATM-IN-13 at 10-20 mg/kg with the same administration method over 16 days, in conjunction with liposomal irinotecan, resulted in 80.8% and 91.1% tumor growth inhibition rates in an SW620 colorectal cancer xenograft model, with satisfactory safety.