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XRD-0394 is a potent and orally active dual ATM and DNA-PKcs inhibitor with IC50s of 0.39 nM and 0.89 nM, respectively. XRD-0394 shows selectivity over other PIKK and PI3K family members. XRD-0394 significantly enhances tumor cell killing in vitro and in vivo under therapeutic ionizing radiation conditions. XRD-0394 can potentiate the effects of PARP and topoisomerase I inhibitors in vitro[1]. | [in vivo]
XRD-0394 (3-10 mg/kg) via oral gavage 45 minutes prior to focal radiotherapy of 0 or 10 Gy and tumors are harvested for target inhibition assessment 1 hour after irradiation, XRD-0394 inhibits the activities of both DNA-PK and ATM kinases in tumors in vivo[1].
Pharmacokinetic analyses show that 10 mg/kg XRD-0394 (oral gavage) resulted in plasma concentration of 840-1,125 ng/mL (1.6-2.1 mM) for 4 hours before declining to undetectable levels by 24 hours in mice[1]. | Animal Model: | Female NCr nu/nu mice [Crl:NU(NCr)-Foxn1nu, Strain 490] were used for MDA-MB-321 subcutaneous tumor implantation, alone or in combination with focal irradiation[1]. | | Dosage: | 3 mg/kg, 6 mg/kg, 10 mg/kg (0.5% HPMC and 0.2% Tween80) | | Administration: | Oral gavage; once daily; for 3 consecutive days | | Result: | Inhibited phosphorylation of the ATM substrate, KAP1, and autophosphorylation of DNA-PK.
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| [References]
[1] Gilmer T M, et al. A novel dual ATM/DNA-PK inhibitor, XRD-0394, potently radiosensitizes and potentiates PARP and topoisomerase I inhibitors[J]. Molecular Cancer Therapeutics, 2024. DOI:10.1158/1535-7163.MCT-23-0890 |
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