DAPT (GSI-IX) (Synonyms: gamma-Secretase Inhibitor IX, 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.