Background
RO4929097 is a small-molecule inhibitor of γ secretase with IC50 of 4 nM and EC50 of 5 nM [1]. It shows no in vitro inhibitory activity on the closely related proteases. It also has greater than 100-fold selectivity with respect to 75 other proteins of various types [1]. RO4929097 binds to γ secretase and inhibits its protease activity, therefore blocking the cleavage of Notch and reducing Notch signaling. Up-regulaton of this signaling pathway promotes tumorigenesis of multiple cancers.
RO4929097 has shown potential antitumor activity both in vitro and in vivo. It impaired the growth of melanoma cell lines and tumor formation of human primary melanoma xenograft [2]. It slowed proliferation and reduces colony formation of breast cancer cell lines[1]. In addition, RO4929097 decreased tumor formation in xenograft models of colorectal, pancreatic, lung cancer and melanoma[1, 2]. RO4929097 has been tested in multiple phase I/II clinical trials in patients with advanced solid tumors, either as monotherapy or in combination with other anti-tumor agents[3-8].
参考文献:
1.?Luistro L, He W, Smith M et al. Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res 2009; 69: 7672-7680.
2.?Huynh C, Poliseno L, Segura MF et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PLoS One 2011; 6: e25264.
3.?Richter S, Bedard PL, Chen EX et al. A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575). Invest New Drugs 2014; 32: 243-249.
4.?Sahebjam S, Bedard PL, Castonguay V et al. A phase I study of the combination of ro4929097 and cediranib in patients with advanced solid tumours (PJC-004/NCI 8503). Br J Cancer 2013; 109: 943-949.
5.?Diaz-Padilla I, Hirte H, Oza AM et al. A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors. Invest New Drugs 2013; 31: 1182-1191.
6.?Tolcher AW, Messersmith WA, Mikulski SM et al. Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol 2012; 30: 2348-2353.
7.?Strosberg JR, Yeatman T, Weber J et al. A phase II study of RO4929097 in metastatic colorectal cancer. Eur J Cancer 2012; 48: 997-1003.
8.?Kolb EA, Gorlick R, Keir ST et al. Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a gamma-secretase inhibitor targeting notch signaling. Pediatr Blood Cancer 2012; 58: 815-818.
Protocol
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Cell experiment: [1]
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Cell lines
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SUM190 and SUM149 cells
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Preparation method
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The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.
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Reaction Conditions
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1 μM, 14 days for 2D cultures 7 days for 3D cultures
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Applications
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After treating with increasing doses of ionizing radiation in the presence or absence of the drug, 2D colonies were allowed to grow for 10–14 days, while the mammospheres were permitted to grow for 1 week. At 1 μM, RO4929097 was able to sensitize adherent cells to radiation with a more significant effect seen in SUM190 than in SUM149 cells. However, the same dose of inhibitor radioprotected cells grown under conditions that favor the enrichment of the cancer stem cells at higher doses of ionizing radiation. This discrepancy between 2D and 3D cultures suggested that cell contact may be needed for a Notch inhibitor to have a significant effect.
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Animal experiment: [2]
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Animal models
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NOD/SCID/IL2gammaR-/- (NOG) mice injected with WM3248 cells
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Dosage form
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Oral administration, 10 mg/Kg/day for 30 days
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Applications
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There was a decrease in tumor growth with RO4929097 treatment, which was more appreciable after tumors were extracted for weight assessment. RO4929097-treated tumors also displayed lower expression of putative melanoma stem cell markers CD166, CD271 and JARID1B compared to vehicle-treated ones.
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Other notes
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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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参考文献:
[1] Debeb B G, Cohen E N, Boley K, et al. Pre-clinical studies of Notch signaling inhibitor RO4929097 in inflammatory breast cancer cells. Breast cancer research and treatment, 2012, 134(2): 495-510.
[2] Huynh C, Poliseno L, Segura M F, et al. The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma. PloS one, 2011, 6(9): e25264.
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