Preclinical assessment of JNJ-26854165 (Serdemetan1), a novel tryptamine compound with radiosensitizing activity in vitro and in tumor xenografts

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 0.25 μM in H460 and at 5 μM in A549 cells resulted in a sensitivity–enhancement ratio of 1.18 and 1.36, respectively. At 2 Gy, surviving fractions were 0.72 and 0.97 for p53-WT HCT116 and p53-null cells exposed to 0.5 μM 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 inhibits clonogenic survival synergistically with radiation in p53-WT tumor cells.
► Serdemetan inhibits proliferation, migration, and capillary formation of endothelial cells.
► Serdemetan enhances radiation-induced tumor growth delay in vivo.
► Serdemetan antitumor effects are associated with activation of p53 pathway and G2/M arrests.
► Lower effects in p53-null tumors suggest alternative molecular mechanisms of activity.