生物活性

• 靶点

  Amyloid-β 40 IC50:115nM

  Amyloid-β 42 IC50:200nM

  γ secretase IC50:20nM

• 描述DAPT is a novel γ-secretase inhibitor with IC50 value of 20nM for inhibition of total Aβ production from HEK 293 cells, and also exhibited inhibitory effect on total Aβ and Aβ42 production in human primary neuronal cultures with IC50 values of 115nM and 200nM, respectively. Total Aβ and Aβ42 were inhibited in a concentration-dependent and reversible manner by DAPT at concentration ranging in 42-625nM for 24h in PDAPP mouse neuronal cultures, without obvious effect on APPα and APPβ levels. DAPT exhibits blood-brain barrier permeable ability, as administration of DAPT (100 mg/kg s.c.) to PDAPP mice led to 45% reduction of cortical Aβ after 3h. Oral administration of DAPT at dose of 10, 30 and 100 mg/kg reduced cortical total Aβ in a dose-dependent manner with a 50% reduction occuring at 100 mg/kg. As γ-secretase cleaves Notch, DAPT is used as an indirect inhibitor of the Notch signaling. The expression of Notch target gene HES1 reduced by 80% in cultured hybrid human–mouse fetal thymus organ culture seeded with CD34⁺ thymocytes at 5 days post DAPT treatment. And this block of Notch signaling by DAPT shifted differentiation into non–T cells in a thymic microenvironment depending on the starting progenitor cells. The inhibition of Notch response by DAPT resulted in enhanced neuronal differentiation of neuralized, embryonic stem (ES) cell-derived embryoid bodies. DAPT could enhance mesodermal induction and subsequent cardiogenesis of murine iPSC through abolishing the inhibitory effect of Nap1l1 and reduction of NICD release during differentiation.
• 作用机制DAPT targets the C-terminal fragment of PS which represents the catalytic center of γ-secretase, especially the transmembrane domain 7 or more C-terminal region. DAPT can completely abolish the proteolytic activity of γ-secretase.^[5][6]
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  A549	10 μM	Growth Inhibition Assay	24h	decreases the cell viability combined with PTE	23671619
  A549 CD133−	2 μM	Growth Inhibition Assay	48 h	enhances cell growth inhibition induced by CDDP	24502949
  A549 CD133+	2 μM	Growth Inhibition Assay	48 h	enhances cell growth inhibition induced by CDDP	24502949

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• 动物研究
  剂量	Mice: 10 mg/kg[7] (s.c.), 100 mg/kg[1] (s.c.); 1 mg/kg - 5 mg/kg[8] (i.p.), 200 mg/kg[9] (i.p.) Rat: 10 mg/kg, 50 mg/kg[10] (i.p.), 0.03 mg/kg[11] (stereotactically injected into lateral cerebral ventricle)
  给药途径	s.c., i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02447809	Coronary Artery Disease	Phase 4	Unknown	December 2016	China, Jiangsu ... more >> First Affiliated Hospital of Nanjing Medical University Recruiting Nanjing, Jiangsu, China, 210029 Contact: Fuming Zhang, M.D.    +86-25-83718836 ext 6360    jsphkj@163.com    Contact: Yi Chai, M.D.    +86-25-83718836 ext 6360    jsphkj@163.com Collapse <<
  NCT03635749	Acute Stroke ... more >>Transient Ischemic Attack Collapse <<	Phase 3	Not yet recruiting	December 30, 2023	-
  NCT01752894	Ischemic Heart Disease	Not Applicable	Unknown	November 2017	Korea, Republic of ... more >> Division of Cardiology, Department of Internal Medicine, Yonsei University College of Medicine Recruiting Seoul, Korea, Republic of, 120-752 Contact: MYEONG-KI HONG, MD    82-2-2228-8458    MKHONG61@yuhs.ac Collapse <<

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• 参考文献

• [1] Dovey HF, John V, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem. 2001 Jan;76(1):173-81.

  [2] De Smedt M, Hoebeke I, et al. Different thresholds of Notch signaling bias human precursor cells toward B-, NK-, monocytic/dendritic-, or T-cell lineage in thymus microenvironment. Blood. 2005 Nov 15;106(10):3498-506. Epub 2005 Jul 19.

  [3] Crawford TQ, Roelink H, et al. The notch response inhibitor DAPT enhances neuronal differentiation in embryonic stem cell-derived embryoid bodies independently of sonic hedgehog signaling. Dev Dyn. 2007 Mar;236(3):886-92.

  [4] Gong H, Yan Y, et al. Knockdown of nucleosome assembly protein 1-like 1 induces mesoderm formation and cardiomyogenesis via notch signaling in murine-induced pluripotent stem cells. Stem Cells. 2014 Jul;32(7):1759-73.

  [5] Morohashi Y, Kan T, et al. C-terminal fragment of presenilin is the molecular target of a dipeptidic gamma-secretase-specific inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester). J Biol Chem. 2006 May 26;281(21):14670-6. Epub 2006 Mar 28.

  [6] Sato C, Morohashi Y, et al. Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines. J Neurosci. 2006 Nov 15;26(46):12081-8.

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