JNJ-26854165

JNJ-26854165 (Serdemetan) is a p53-activating agent with antiproliferative activity in various p53 wild-type (WT) tumor cell lines. JNJ-26854165 inhibited clonogenic survival in all cell lines, but in a lower extent in p53-null-HCT116. JNJ-26854165 also inhibited proliferation, capillary tube formation and migration of HMEC-1 cells. JNJ-26854165 demonstrated cytotoxic activity in vitro. In vivo, JNJ-26854165 (Serdemetan) caused a greater than additive increase in tumor growth delay. 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 in vivo. JNJ-26854165 (Serdemetan) treatment at 0.25μM in H460 and at 5μM in A549 cells resulted in a sensitivity-enhancement ratio of 1.18 and 1.36, respectively. JNJ-26854165 treatment induced p53-mediated apoptosis in acute leukemia cells with wild-type p53, in which p53 rapidly drives transcription-independent apoptosis followed by activation of a transcription-dependent pathway. JNJ-26854165 accelerated the proteasome-mediated degradation of p21 and antagonized the transcriptional induction of p21 by p53. JNJ-26854165 is currently being evaluated in Phase I clinical trials.