JNJ-26854165 (Serdemetan)

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

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

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.

Initial testing of JNJ-26854165 (Serdemetan) by the pediatric preclinical testing program.[Pubmed:21922647]

Pediatr Blood Cancer. 2012 Aug;59(2):329-32.

JNJ-26854165 was originally developed as an activator of p53 capable of inducing apoptosis in cancer cell lines. In vitro, JNJ-26854165 demonstrated cytotoxic activity. The ALL cell line panel had a significantly lower median IC(50) (0.85 microM) than the remaining cell lines. In vivo JNJ-26854165 induced significant differences in EFS distribution compared to control in 18 of 37 solid tumors and in 5 of 7 of the evaluable ALL xenografts. Objective responses were observed in 4 of 37 solid tumor xenografts, and 2 of 7 ALL xenografts achieved PR or CR. Responses were noted in xenografts with both mutant and wild-type p53.

Preclinical assessment of JNJ-26854165 (Serdemetan), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts.[Pubmed:21937165]

Cancer Lett. 2011 Dec 22;312(2):209-18.

Serdemetan (JNJ-26854165) is a novel tryptamine compound with antiproliferative activity in various p53 wild-type (WT) tumor cell lines. We investigated its potential as radiosensitizer using four human cancer cell lines: H460, A549, p53-WT-HCT116, and p53-null-HCT116. Serdemetan inhibited clonogenic survival in all cell lines, but in a lower extent in p53-null-HCT116. In the combination studies, Serdemetan treatment at 0.25muM in H460 and at 5muM in A549 cells resulted in a sensitivity-enhancement ratio of 1.18 and 1.36, respectively. At 2Gy, surviving fractions were 0.72 and 0.97 for p53-WT HCT116 and p53-null cells exposed to 0.5muM of Serdemetan, respectively (p<0.05). Radiosensitization of H460 and A549 cells was associated with G2/M cell cycle arrest and with an increased expression of p53 and p21. In vivo, Serdemetan caused a greater than additive increase in tumor growth delay. The dose enhancement factor was 1.9 and 1.6 for H460 and A549 tumors, respectively. Serdemetan inhibited proliferation, capillary tube formation and migration of HMEC-1 cells. These effects were more marked concurrently with irradiation. These results in tumor and endothelial cells suggest that Serdemetan has potential as a radiosensitizer. Further investigations are warranted with regard to the molecular mechanisms underlying its actions and its dependency regarding p53 status.

Serdemetan(JNJ-26854165) acts as a HDM2 ubiquitin ligase antagonist and also induces early apoptosis in p53 wild-type cells, inhibits cellular proliferation followed by delayed apoptosis in the absence of functional p53.

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