DAPT (GSI-IX)

DAPT (GSI-IX) is an orally active γ-secretase inhibitor with IC50s of 115 nM and 200 nM for total amyloid-β (Aβ) and Aβ42 produced in human primary neuronal cultures, respectively.^[1]

In vitro experiment it indicated that treatment with 10 μM DAPT significantly reduced the expression of Il6, Il12 and iNos at 6 and 12 h compared with vehicle at both low- and high-LPS stimulation.^[2] In vitro, with 25, 50, and 100 μM DAPT in HepG2 cells significantly inhibited the proliferation and migration ability of HepG2 cells.^[3] In vitro test shown it that treatment with 0, 25, 50 and 75 μM DAPT in CNE-2 cells, pre-treatment with DAPT enhanced the effect of cisplatin in a dose-dependent manner. However, the CNE-2 cells were treated with increasing concentrations of DAPT, and there was no obvious effect on cell survival.^[5]

In vivo efficacy study it shown that treatment with 100 mg/kg DAPT subcutaneously in PDAPP mice, after 3 h the peak level of DAPT were 490 ng/g in the brain, and levels greater than 100 ng/g were sustained throughout the first 18 h.^[1] DAPT (10, 30 and 100 mg/kg; p.o.) reduced the cortical total Aβ in a dose-dependent manner with a 50% reduction occuring at 100 mg/kg dosing.^[1] In vivo test indicated it that DAPT was administered intragastrically once daily for 28 days in ICR mice that can effectively in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, because of DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests.^[4]

References:
[1].Dovey HF, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. 2001 Jan;76(1):173-81.
[2].Hans CP, et al. DAPT, a potent Notch inhibitor regresses actively growing abdominal aortic aneurysm via divergent pathways. Clin Sci (Lond). 2020 Jun 26;134(12):1555-1572.
[3].Qiu K, et al. DAPT suppresses proliferation and migration of hepatocellular carcinoma by regulating the extracellular matrix and inhibiting the Hes1/PTEN/AKT/mTOR signaling pathway. J Gastrointest Oncol. 2021 Jun;12(3):1101-1116.
[4].Yang JY, et al. DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis. Front Pharmacol. 2022 Apr 29;13:902796.
[5].Zhou JX, et al. γ-secretase inhibition combined with cisplatin enhances apoptosis of nasopharyngeal carcinoma cells. Exp Ther Med. 2012 Feb;3(2):357-361.

DAPT (GSI-IX) 是一种具有口服活性的 γ-分泌酶抑制剂，对人原代神经元培养物中产生的总淀粉样蛋白-β (Aβ) 和 Aβ42 的 IC50 分别为 115 nM 和 200 nM。^[1]

体外实验表明，在低和高 LPS 刺激下，与载体相比，10 μM DAPT 在 6 和 12 h 显着降低了 Il6、Il12 和 iNos 的表达。^[2] 在体外，25、50、100 μM DAPT对HepG2细胞有显着抑制HepG2细胞增殖和迁移能力的作用。^[3] 体外试验表明，0、25、 50 和 75 μM DAPT 在 CNE-2 细胞中，用 DAPT 预处理以剂量依赖的方式增强了顺铂的作用。然而，CNE-2细胞经增加浓度的DAPT后，对细胞存活无明显影响。^[5]

体内功效研究表明，在 PDAPP 小鼠中皮下注射 100 mg/kg DAPT，3 小时后大脑中 DAPT 的峰值水平为 490 ng/g，并且在整个过程中持续保持大于 100 ng/g 的水平前 18 小时。^[1] DAPT（10、30 和 100 mg/kg；口服）以剂量依赖性方式降低皮质总 Aβ，在 100 mg/kg 时降低 50% ^[1] 体内试验表明，ICR小鼠每天1次灌胃DAPT，连续给药28天，可有效改善Cd诱导的小鼠多器官损伤和认知障碍，因为DAPT 恢复了 Y 迷宫、强迫游泳和莫里斯水迷宫 (MWM) 测试中的异常表现。^[4]