TY - JOUR TI - A subset of CB002 xanthine analogs bypass p53-signaling to restore a p53 transcriptome and target an S-phase cell cycle checkpoint in tumors with mutated-p53 AU - Hernandez Borrero, Liz AU - Dicker, David T AU - Santiago, John AU - Sanders, Jennifer AU - Tian, Xiaobing AU - Ahsan, Nagib AU - Lev, Avital AU - Zhou, Lanlan AU - El-Deiry, Wafik S A2 - Zaidi, Mone VL - 10 PY - 2021 DA - 2021/07/29 SP - e70429 C1 - eLife 2021;10:e70429 DO - 10.7554/eLife.70429 UR - https://doi.org/10.7554/eLife.70429 AB - Mutations in TP53 occur commonly in the majority of human tumors and confer aggressive tumor phenotypes, including metastasis and therapy resistance. CB002 and structural-analogs restore p53 signaling in tumors with mutant-p53 but we find that unlike other xanthines such as caffeine, pentoxifylline, and theophylline, they do not deregulate the G2 checkpoint. Novel CB002-analogs induce pro-apoptotic Noxa protein in an ATF3/4-dependent manner, whereas caffeine, pentoxifylline, and theophylline do not. By contrast to caffeine, CB002-analogs target an S-phase checkpoint associated with increased p-RPA/RPA2, p-ATR, decreased Cyclin A, p-histone H3 expression, and downregulation of essential proteins in DNA-synthesis and DNA-repair. CB002-analog #4 enhances cell death, and decreases Ki-67 in patient-derived tumor-organoids without toxicity to normal human cells. Preliminary in vivo studies demonstrate anti-tumor efficacy in mice. Thus, a novel class of anti-cancer drugs shows the activation of p53 pathway signaling in tumors with mutated p53, and targets an S-phase checkpoint. KW - p53 KW - cancer KW - therapy KW - xanthines KW - CB002 KW - noxa JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -