{"doi":"10.1021/acsptsci.2c00147","title":"Discovery of Novel Small-Molecule Scaffolds for the Inhibition and Activation of WIP1 Phosphatase from a RapidFire Mass Spectrometry High-Throughput Screen","abstract":"or PP2Cδ, is a serine/threonine protein phosphatase induced by P53 after genotoxic stress. WIP1 inhibition has been proposed as a therapeutic strategy for P53 wild-type cancers in which it is overexpressed, but this approach would be ineffective in P53-negative cancers. Furthermore, there are several cancers with mutated P53 where WIP1 acts as a tumor suppressor. Therefore, activating WIP1 phosphatase might also be a therapeutic strategy, depending on the P53 status. To date, no specific, potent WIP1 inhibitors with appropriate pharmacokinetic properties have been reported, nor have WIP1-specific activators. Here, we report the discovery of new WIP1 modulators from a high-throughput screen (HTS) using previously described orthogonal biochemical assays suitable for identifying both inhibitors and activators. The primary HTS was performed against a library of 102 277 compounds at a single concentration using a RapidFire mass spectrometry assay. Hits were further evaluated over a range of 11 concentrations with both the RapidFire MS assay and an orthogonal fluorescence-based assay. Further biophysical, biochemical, and cell-based studies of confirmed hits revealed a WIP1 activator and two inhibitors, one competitive and one uncompetitive. These new scaffolds are prime candidates for optimization which might enable inhibitors with improved pharmacokinetics and a first-in-class WIP1 activator.","journal":"ACS Pharmacology & Translational Science","year":2022,"id":273208,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9586,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":317767,"name":"Yuhong Fang","orcid":"0000-0001-6742-5677","position":1,"is_corresponding":false},{"id":317766,"name":"Dingyin Tao","orcid":"0000-0001-6531-2740","position":2,"is_corresponding":false},{"id":940236,"name":"Harichandra D. Tagad","orcid":"0000-0003-1595-6665","position":3,"is_corresponding":false},{"id":332246,"name":"Hongmao Sun","orcid":"0000-0003-4042-6498","position":4,"is_corresponding":false},{"id":940237,"name":"Yuhong Wang","orcid":"0000-0001-6480-9528","position":5,"is_corresponding":false},{"id":700096,"name":"Karavadhi Surendra","orcid":null,"position":6,"is_corresponding":false},{"id":687483,"name":"Kelly Lane","orcid":null,"position":7,"is_corresponding":false},{"id":663567,"name":"Zhendan Shi","orcid":"0000-0002-0463-3652","position":8,"is_corresponding":false},{"id":687057,"name":"Olga Vasalatiy","orcid":"0000-0002-7200-2959","position":9,"is_corresponding":false},{"id":418344,"name":"Christopher A. LeClair","orcid":"0000-0002-2746-5938","position":10,"is_corresponding":false},{"id":931601,"name":"Rebecca Eells","orcid":null,"position":11,"is_corresponding":false},{"id":239789,"name":"Min Shen","orcid":"0000-0002-8218-0433","position":12,"is_corresponding":false},{"id":353889,"name":"Samarjit Patnaik","orcid":"0000-0002-4265-7620","position":13,"is_corresponding":false},{"id":383717,"name":"Ettore Appella","orcid":"0000-0003-0569-9722","position":14,"is_corresponding":false},{"id":740050,"name":"Nathan P. Coussens","orcid":"0000-0002-3896-7909","position":15,"is_corresponding":false},{"id":255126,"name":"Matthew D. Hall","orcid":"0000-0002-5073-442X","position":16,"is_corresponding":false},{"id":383718,"name":"Daniel H. Appella","orcid":"0000-0001-7195-7764","position":17,"is_corresponding":false},{"id":487249,"name":"Victor Clausse","orcid":"0000-0002-9080-4365","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T00:27:52.048702Z","pmid":"36268125","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":[]}