An antagonist of MDM2 action
JNJ-26854165, also named as Serdemetan, is originally developed as an activator of p53, is now regarded as a novel oral Human Double Minute-2 (HDM-2) ubiquitin ligase antagonist. It can increase the level of HDM-2 client proteins, such as p53, by inhibiting the association of HDM-2-client protein complex with the proteosome. It is demonstrated potent anti-proliferative and apoptosis-inducing activity of JNJ-26854165 in a broad range of p53 wild type and mutant tumor models. In vivo, JNJ-26854165 may induce important differences in EFS distribution when comparing to control in 18 of 37 solid tumors and in 5 of 7 of the evaluable ALL xenografts.
Reference
[1].J. Tabernero, L. Dirix, P. Schoffski, A. Cervantes, J. Capdevila, J. Baselga, L. van Beijsterveldt, H. Winkler, S. Kraljevic and S. H. Zhuang. Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of HDM-2 antagonist JNJ-26854165 in patients with advanced refractory solid tumors. Journal of Clinical Oncology (Meeting Abstracts) May 2009 vol. 27 no. 15S 3514
[2].Malcolm A. Smith, Richard Gorlick, E. Anders Kolb, Richard Lock, Hernan Carol, John M. Maris, Stephen T. Keir, Christopher L. Morton, C. Patrick Reynolds, Min H. Kang, Janine Arts, Tarig Bashir, Michel Janicot, Raushan T. Kurmasheva, Peter J. Houghton. Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program. Pediatric Blood & Cancer. Volume 59, Issue 2, pages 329–332, August 2012.
| Cell experiment [1]: | |
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Cell lines |
H460, A549 cells, and HMEC-1 endothelial cells |
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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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Reacting condition |
0.5, 1, 2.5, 5, 10, 25 and 50 μM; 48 h |
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Applications |
After 48 h treatment, Serdemetan inhibited cell proliferation with IC50 values of 3.9 μM, and 8.7 μM for H460 cells and A549 cells, respectively. Moreover, Serdemetan at 5 μM inhibited HMEC-1 endothelial cell migration. |
| Animal experiment [1]: | |
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Animal models |
H460 and A549 cells, injected in the right flank of nude mice were grown as tumor xenografts. |
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Dosage form |
50 mg/kg; p.o. twice a week, for 2 weeks |
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Applications |
Serdemetan treatment significantly enhanced radiation-induced growth delays in A549 and H460 xenograft tumors. |
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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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参考文献: 1. Chargari, C., Leteur, C., Angevin, E., Bashir, T., Schoentjes, B., Arts, J., Janicot, M., Bourhis, J. and Deutsch, E. (2011) Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts. Cancer Lett. 312, 209-218 | |
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