{"doi":"10.1101/2021.07.08.451586","title":"Cellular toxicity of iHAP1 and DT-061 does not occur through PP2A-B56 targeting","abstract":"Abstract PP2A is an abundant phosphoprotein phosphatase that acts as a tumor suppressor. For this reason, compounds able to activate PP2A are attractive anticancer agents. The small molecule compounds iHAP1 and DT-061 have recently been reported by Leonard et al. (2020) and Morita et al. (2020) in Cell to selectively stabilize specific PP2A-B56 complexes which mediate cell killing. Here, we show that this is not the case and question key findings in these papers. Through genome wide CRISPR-Cas9 screens, we uncover the biological pathways targeted by these compounds. We find that iHAP1 directly blocks microtubule assembly both in vitro and in vivo and thus acts as a microtubule poison. In contrast, DT-061 disrupts both the Golgi apparatus and the endoplasmic reticulum and we directly visualize DT-061 in cytoplasmic granules that co-localize with Golgi markers. Our work demonstrates that iHAP1 and DT-061 cannot be used for dissecting PP2A-B56 biology.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":217640,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"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":814566,"name":"Joana Duro","orcid":"0000-0002-2608-4420","position":1,"is_corresponding":false},{"id":814567,"name":"Girish Rajendraprasad","orcid":"0000-0003-2521-3005","position":2,"is_corresponding":false},{"id":274547,"name":"Emil Peter Thrane Hertz","orcid":"0000-0001-6996-3559","position":3,"is_corresponding":false},{"id":814568,"name":"Lya Katrine Kauffeldt Holland","orcid":"0000-0001-5386-5022","position":4,"is_corresponding":false},{"id":586784,"name":"Melanie Weisser","orcid":"0000-0003-3946-3929","position":5,"is_corresponding":false},{"id":575848,"name":"Brennan C McEwan","orcid":"0000-0002-9545-1087","position":6,"is_corresponding":false},{"id":274546,"name":"Blanca López‐Méndez","orcid":"0000-0001-8541-4904","position":7,"is_corresponding":false},{"id":586786,"name":"Guillermo Montoya","orcid":"0000-0002-8269-3941","position":8,"is_corresponding":false},{"id":814569,"name":"Niels Mailand","orcid":"0000-0002-6623-709X","position":9,"is_corresponding":false},{"id":814570,"name":"Kenji Maeda","orcid":"0000-0002-9080-5691","position":10,"is_corresponding":false},{"id":273955,"name":"Arminja N. Kettenbach","orcid":"0000-0003-3979-4576","position":11,"is_corresponding":false},{"id":814571,"name":"Marin Barišić","orcid":"0000-0001-7587-3867","position":12,"is_corresponding":false},{"id":274550,"name":"Jakob Nilsson","orcid":"0000-0003-4100-1125","position":13,"is_corresponding":false},{"id":814565,"name":"Gianmatteo Vit","orcid":"0000-0002-3111-0769","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-18T23:53:20.374789Z","pmid":null,"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":[]}