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- YO-01027 (Dibenzazepine, DBZ)
YO-01027 (Dibenzazepine, DBZ)
YO-01027, also known as dibenzazepine or DBZ, is a potent inhibitor of γ-secretase, a multisubunit aspartyl protease catalyzing the cleavage of numerous type I integral membrane proteins (such as amyloid precursor protein (APP) and Notch). YO-01027 also potently blocks amyloid precursor protein-like (APPL) and Notch cleavage, with estimated inhibition constant IC50 of 2.640.30 nM and 2.920.22 nM respectively, through interaction with the N-terminal fragment of Presenilin in a dose-response manner. Recent studies show that YO-01027-induced inhibition Notch signaling pathway leads to a rapid conversion of proliferative crypt cells into postmitotic cells and impairs MUC16 biosynthesis in a concentration-dependent manner in undifferentiated cells instead of postmiotic stratified cells at both preconfluent and confluent stages.
Reference
Linjie Xiong, Ashley M. Woodward, and Pablo Argueso. Notch signaling modulates MUC16 biosynthesis in an vitro model of human corneal and conjunctival epithelial cell differentiation. Invest. Ophthalmol. Vis. Sci. 2011, 52(8), 5641-5646
Casper Groth, W. Gregory Alvord, Octavio A. Quinones, and Mark E. Fortini. Pharmacological analysis of drosphila melanogaster γ-secretase with respect to differential proteolysis of Notch and APP. Mol. Pharmacol. 2010, 77(4), 567-574
- 1. Yu-Hwai Tsai, Angeline Wu, et al. "Acquisition of NOTCH dependence is a hallmark of human intestinal stem cell maturation." Stem Cell Reports. 2022 May 10;17(5):1138-1153. PMID: 35395175
- 2. Ireland AS, Micinski AM, et al. "MYC Drives Temporal Evolution of Small Cell Lung Cancer Subtypes by Reprogramming Neuroendocrine Fate." Cancer Cell. 2020;S1535-6108(20)30218-X. PMID: 32473656
- 3. Zhu M, Li Y, et al. "Effects of bisphenol A and its alternative bisphenol F on Notch signaling and intestinal development: A novel signaling by which bisphenols disrupt vertebrate development." Environ Pollut. 2020;263(Pt B):114443. PMID: 32311622
- 4. Zhu M, Niu Y, et al. "Low Concentrations of Tetrabromobisphenol A Disrupt Notch Signaling and Intestinal Development in in Vitro and in Vivo Models." Chem Res Toxicol. 2020;10.1021/acs.chemrestox.9b00528. PMID: 32041402
- 5. Idowu J, Home T, et al. "Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease." Sci Rep. 2018 Feb 20;8(1):3340. PMID: 29463793
| Physical Appearance | A solid |
| Storage | Store at -20°C |
| M.Wt | 463.48 |
| Cas No. | 209984-56-5 |
| Formula | C26H23F2N3O3 |
| Synonyms | gamma-Secretase Inhibitor XX,YO01027 |
| Solubility | ≥23.17 mg/mL in DMSO; insoluble in H2O; ≥4.13 mg/mL in EtOH with gentle warming and ultrasonic |
| Chemical Name | (2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]-N-[(7S)-5-methyl-6-oxo-7H-benzo[d][1]benzazepin-7-yl]propanamide |
| SDF | Download SDF |
| Canonical SMILES | CC(C(=O)NC1C2=CC=CC=C2C3=CC=CC=C3N(C1=O)C)NC(=O)CC4=CC(=CC(=C4)F)F |
| Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
| General tips | We do not recommend long-term storage for the solution, please use it up soon. |
| Kinase experiment [1]: | |
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Pharmacological inhibition of γ-secretase activity |
For YO-01027, pilot experiments were performed with different drug concentrations ranging from 0.1 nM to 150 μM to determine the effective linear range and maximal inhibition dose for YO-01027. YO-01027 were added at the required concentrations to the S2 cell medium upon induction of Notch or APPL expression, 6 hrs before protein harvesting. For each sample, YO-01027 was also included at the corresponding concentration in the lysis buffer for protein extraction and immunoblot analysis. |
| Cell experiment [2]: | |
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Cell lines |
Breast cancer stem cells (BCSCs) |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
10 μM; 3 days |
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Applications |
YO-01027 (10 μM) reduced BCSC number and activity. |
| Animal experiment [3]: | |
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Animal models |
C57BL/6 mice |
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Dosage form |
0, 3, 10 and 30 μmol/kg; i.p.; q.d., for 5 days |
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Applications |
In C57BL/6 mice, YO-01027 treatment inhibited epithelial cell proliferation and induced goblet cell differentiation in intestinal adenomas in a dose-dependent manner. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Casper Groth, W. Gregory Alvord, Octavio A. Quinones, and Mark E. Fortini. Pharmacological analysis of drosphila melanogaster γ-secretase with respect to differential proteolysis of Notch and APP. Mol. Pharmacol. 2010, 77(4), 567-574. [2]. Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, Bundred NJ, Clarke RB. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res. 2010 Jan 15;70(2):709-18. [3]. van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005 Jun 16;435(7044):959-63. |
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| Description | YO-01027 (Dibenzazepine, DBZ) is a dipeptidic inhibitor of γ-secretase with IC50 of 2.6 nM and 2.9 nM for APPL and Notch cleavage, respectively. | |||||
| Targets | APPL | Notch | ||||
| IC50 | 2.6 nM | 2.9 nM | ||||
Quality Control & MSDS
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