{"doi":"10.7554/elife.70429","title":"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","abstract":"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.","journal":"eLife","year":2021,"id":190176,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":495334,"name":"David T. Dicker","orcid":"0000-0002-0610-8317","position":1,"is_corresponding":false},{"id":675504,"name":"John Santiago","orcid":"0000-0003-3692-3176","position":2,"is_corresponding":false},{"id":675506,"name":"Jennifer A. Sanders","orcid":"0000-0002-4714-5114","position":3,"is_corresponding":false},{"id":569288,"name":"Xiaobing Tian","orcid":null,"position":4,"is_corresponding":false},{"id":568422,"name":"Nagib Ahsan","orcid":"0000-0002-6813-7527","position":5,"is_corresponding":false},{"id":495332,"name":"Avital Lev","orcid":"0000-0002-2127-7338","position":6,"is_corresponding":false},{"id":495331,"name":"Lanlan Zhou","orcid":"0000-0001-9471-9099","position":7,"is_corresponding":false},{"id":94964,"name":"Wafik S. El‐Deiry","orcid":"0000-0002-9577-8266","position":8,"is_corresponding":false},{"id":625160,"name":"Liz Hernandez Borrero","orcid":"0000-0003-4249-5358","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-18T23:49:22.671571Z","pmid":"34324416","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}