AZD1390 是一种强效、高选择性、口服生物可利用的脑渗透性 ATM 抑制剂，在细胞中的 IC50 为 0.78 nM。
AZD1390 is a potent and selective ATM inhibitor with the ability to cross the blood-brain barrier suitable for the treatment of intracranial malignancies.AZD1390 is an exceptionally potent inhibitor of ATM in cells (IC50 = 0.78 nM) with >10,000-fold selectivity over closely related members of the PIKK family of enzymes and excellent selectivity across a broad panel of kinases.
AZD1390 displays excellent oral bioavailability in preclinical species (66% in rat and 74% in dog), is not a substrate for human efflux transporters, and has been shown to efficiently cross the BBB in non-human primate PET studies.
Reference:
http://mct.aacrjournals.org/content/17/1_Supplement/A124
Animal experiment: | Mouse GL261 glioma (p53 mutant) cells are implanted intra-cranially into immunocompetent, syngeneic C57/bl6 mice followed by bioluminescent imaging (BLI) prior to randomization. AZD1390 is administered by oral gavage prior to deliver multiple fractions of 2-3 Gy of radiation on 2 to 4 consecutive days. Radiation is administered via small animal radiation research platform (SARRP) irradiation to the site of the tumor with a 5×5 mm lateral ?eld[2]. |
参考文献: [1]. Durant ST, et al. The brain-penetrant clinical ATM inhibitor AZD1390 radiosensitizes and improves survival of preclinical brain tumor models. Sci Adv. 2018 Jun 20;4(6):eaat1719. | |
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