{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:19:20Z","timestamp":1772173160018,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010263","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:00:00Z","timestamp":1686182400000}}],"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T00:00:00Z","timestamp":1685059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U54HL127624"],"award-info":[{"award-number":["U54HL127624"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U24TR002278"],"award-info":[{"award-number":["U24TR002278"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U01LM012630"],"award-info":[{"award-number":["U01LM012630"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Sylvester Comprehensive Cancer Center Support Grant","award":["P30CA240139"],"award-info":[{"award-number":["P30CA240139"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>PNCK, or CAMK1b, is an understudied kinase of the calcium-calmodulin dependent kinase family which recently has been identified as a marker of cancer progression and survival in several large-scale multi-omics studies. The biology of PNCK and its relation to oncogenesis has also begun to be elucidated, with data suggesting various roles in DNA damage response, cell cycle control, apoptosis and HIF-1-alpha related pathways. To further explore PNCK as a clinical target, potent small-molecule molecular probes must be developed. Currently, there are no targeted small molecule inhibitors in pre-clinical or clinical studies for the CAMK family. Additionally, there exists no experimentally derived crystal structure for PNCK. We herein report a three-pronged chemical probe discovery campaign which utilized homology modeling, machine learning, virtual screening and molecular dynamics to identify small molecules with low-micromolar potency against PNCK activity from commercially available compound libraries. We report the discovery of a hit-series for the first targeted effort towards discovering PNCK inhibitors that will serve as the starting point for future medicinal chemistry efforts for hit-to-lead optimization of potent chemical probes.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010263","type":"journal-article","created":{"date-parts":[[2023,5,26]],"date-time":"2023-05-26T13:30:38Z","timestamp":1685107838000},"page":"e1010263","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["AI-Assisted chemical probe discovery for the understudied Calcium-Calmodulin Dependent Kinase, PNCK"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2779-1992","authenticated-orcid":true,"given":"Derek J.","family":"Essegian","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valery","family":"Chavez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabia","family":"Khurshid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaime R.","family":"Merchan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan C.","family":"Sch\u00fcrer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,5,26]]},"reference":[{"issue":"7","key":"pcbi.1010263.ref001","doi-asserted-by":"crossref","first-page":"100128","DOI":"10.1016\/j.xcrm.2020.100128","article-title":"The Clinical Kinase Index: A Method to Prioritize Understudied Kinases as Drug Targets for the Treatment of Cancer","volume":"1","author":"D Essegian","year":"2020","journal-title":"Cell Rep Med"},{"issue":"D1","key":"pcbi.1010263.ref002","doi-asserted-by":"crossref","first-page":"D995","DOI":"10.1093\/nar\/gkw1072","article-title":"Pharos: Collating protein information to shed light on the druggable genome","volume":"45","author":"DT Nguyen","year":"2017","journal-title":"Nucleic Acids Res"},{"issue":"5","key":"pcbi.1010263.ref003","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrd.2018.14","article-title":"Unexplored therapeutic opportunities in the human genome","volume":"17","author":"TI Oprea","year":"2018","journal-title":"Nat Rev Drug Discov"},{"issue":"17","key":"pcbi.1010263.ref004","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1007\/s00018-008-8086-2","article-title":"Ca(2+)\/calmodulin-dependent protein kinases.","volume":"65","author":"MT Swulius","year":"2008","journal-title":"Cell Mol Life Sci"},{"issue":"12","key":"pcbi.1010263.ref005","doi-asserted-by":"crossref","first-page":"5408","DOI":"10.1158\/0008-5472.CAN-05-0271","article-title":"Calcium\/calmodulin-dependent kinase I and calcium\/calmodulin-dependent kinase kinase participate in the control of cell cycle progression in MCF-7 human breast cancer cells","volume":"65","author":"OG Rodriguez-Mora","year":"2005","journal-title":"Cancer Res"},{"issue":"4","key":"pcbi.1010263.ref006","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1517\/14728222.9.4.791","article-title":"Calcium\/calmodulin-dependent protein kinases as potential targets in cancer therapy","volume":"9","author":"O Rodriguez-Mora","year":"2005","journal-title":"Expert Opin Ther Targets"},{"issue":"5","key":"pcbi.1010263.ref007","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.3892\/mmr.2014.2525","article-title":"Calcium\/calmodulindependent protein kinase II enhances metastasis of human gastric cancer by upregulating nuclear factorkappaB and Aktmediated matrix metalloproteinase9 production","volume":"10","author":"Z Liu","year":"2014","journal-title":"Mol Med Rep"},{"key":"pcbi.1010263.ref008","doi-asserted-by":"crossref","first-page":"21","DOI":"10.3389\/fphar.2014.00021","article-title":"CaMKII inhibitors: from research tools to therapeutic agents.","volume":"5","author":"P Pellicena","year":"2014","journal-title":"Front Pharmacol"},{"issue":"1","key":"pcbi.1010263.ref009","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.molcel.2018.08.014","article-title":"LncRNA CamK-A Regulates Ca(2+)-Signaling-Mediated Tumor Microenvironment Remodeling.","volume":"72","author":"LJ Sang","year":"2018","journal-title":"Mol Cell"},{"issue":"2","key":"pcbi.1010263.ref010","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/0955-0674(93)90111-3","article-title":"The multifunctional Ca2+\/calmodulin-dependent protein kinases","volume":"5","author":"H. Schulman","year":"1993","journal-title":"Curr Opin Cell Biol"},{"issue":"10","key":"pcbi.1010263.ref011","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1101\/gr.254276.119","article-title":"A novel assay to screen siRNA libraries identifies protein kinases required for chromosome transmission","volume":"29","author":"M Liskovykh","year":"2019","journal-title":"Genome Res"},{"issue":"10","key":"pcbi.1010263.ref012","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/ng.2764","article-title":"The Cancer Genome Atlas Pan-Cancer analysis project","volume":"45","author":"Cancer Genome Atlas Research N","year":"2013","journal-title":"Nat Genet"},{"issue":"12","key":"pcbi.1010263.ref013","doi-asserted-by":"crossref","first-page":"105621","DOI":"10.1016\/j.isci.2022.105621","article-title":"Cellular and molecular effects of PNCK, a non-canonical kinase target in renal cell carcinoma","volume":"25","author":"DJ Essegian","year":"2022","journal-title":"iScience"},{"issue":"2","key":"pcbi.1010263.ref014","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/prot.10613","article-title":"A hierarchical approach to all-atom protein loop prediction","volume":"55","author":"MP Jacobson","year":"2004","journal-title":"Proteins"},{"issue":"1","key":"pcbi.1010263.ref015","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nprot.2008.197","article-title":"Protein structure homology modeling using SWISS-MODEL workspace","volume":"4","author":"L Bordoli","year":"2009","journal-title":"Nat Protoc"},{"issue":"1","key":"pcbi.1010263.ref016","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1107\/S0907444909042073","article-title":"MolProbity: all-atom structure validation for macromolecular crystallography","volume":"66","author":"VB Chen","year":"2010","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"issue":"7873","key":"pcbi.1010263.ref017","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"J Jumper","year":"2021","journal-title":"Nature"},{"issue":"8","key":"pcbi.1010263.ref018","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1007\/s10822-012-9584-8","article-title":"FRED and HYBRID docking performance on standardized datasets","volume":"26","author":"M. McGann","year":"2012","journal-title":"J Comput Aided Mol Des"},{"key":"pcbi.1010263.ref019","doi-asserted-by":"crossref","first-page":"16924","DOI":"10.1038\/srep16924","article-title":"Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4.","volume":"5","author":"BK Allen","year":"2015","journal-title":"Sci Rep."},{"issue":"D1","key":"pcbi.1010263.ref020","doi-asserted-by":"crossref","first-page":"D158","DOI":"10.1093\/nar\/gkw1099","article-title":"UniProt: the universal protein knowledgebase","volume":"45","author":"C. The UniProt","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010263.ref021","doi-asserted-by":"crossref","first-page":"W695","DOI":"10.1093\/nar\/gkq313","article-title":"A new bioinformatics analysis tools framework at EMBL-EBI","volume":"38","author":"M Goujon","year":"2010","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"pcbi.1010263.ref022","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1002\/pro.355","article-title":"An enriched structural kinase database to enable kinome-wide structure-based analyses and drug discovery","volume":"19","author":"N Brooijmans","year":"2010","journal-title":"Protein Sci"},{"key":"pcbi.1010263.ref023","article-title":"Kinome-wide activity classification of small molecules by deep learning.","author":"BK Allen","year":"2019","journal-title":"bioRxiv."},{"issue":"9","key":"pcbi.1010263.ref024","doi-asserted-by":"crossref","first-page":"e44828","DOI":"10.1371\/journal.pone.0044828","article-title":"Crystal structures of human CaMKIalpha reveal insights into the regulation mechanism of CaMKI.","volume":"7","author":"M Zha","year":"2012","journal-title":"PLoS One"},{"issue":"5","key":"pcbi.1010263.ref025","first-page":"883","article-title":"Activation of calcium\/calmodulin regulated kinases","volume":"46","author":"M Wilmann","year":"2000","journal-title":"Cell Mol Biol (Noisy-le-grand)."},{"issue":"19","key":"pcbi.1010263.ref026","first-page":"5571","article-title":"The caM kinase, Pnck, is spatially and temporally regulated during murine mammary gland development and may identify an epithelial cell subtype involved in breast cancer","volume":"60","author":"HP Gardner","year":"2000","journal-title":"Cancer Res"},{"issue":"2","key":"pcbi.1010263.ref027","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1006\/geno.1999.6091","article-title":"Cloning, characterization, and chromosomal localization of Pnck, a Ca(2+)\/calmodulin-dependent protein kinase.","volume":"63","author":"HP Gardner","year":"2000","journal-title":"Genomics"},{"issue":"1","key":"pcbi.1010263.ref028","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1021\/jm501603h","article-title":"Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors","volume":"58","author":"RS Vijayan","year":"2015","journal-title":"J Med Chem"},{"issue":"D1","key":"pcbi.1010263.ref029","doi-asserted-by":"crossref","first-page":"D654","DOI":"10.1093\/nar\/gkab920","article-title":"Kincore: a web resource for structural classification of protein kinases and their inhibitors","volume":"50","author":"V Modi","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pcbi.1010263.ref030","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1021\/ci300403k","article-title":"Kinome-wide activity modeling from diverse public high-quality data sets.","volume":"53","author":"SC Schurer","year":"2013","journal-title":"J Chem Inf Model"},{"issue":"Database issue","key":"pcbi.1010263.ref031","doi-asserted-by":"crossref","first-page":"D1083","DOI":"10.1093\/nar\/gkt1031","article-title":"The ChEMBL bioactivity database: an update","volume":"42","author":"AP Bento","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pcbi.1010263.ref032","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1021\/jm0306430","article-title":"Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy","volume":"47","author":"RA Friesner","year":"2004","journal-title":"J Med Chem"},{"issue":"3","key":"pcbi.1010263.ref033","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0169-409X(02)00008-X","article-title":"Prediction of drug solubility from structure","volume":"54","author":"WL Jorgensen","year":"2002","journal-title":"Adv Drug Deliv Rev"},{"issue":"15","key":"pcbi.1010263.ref034","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1002\/j.1460-2075.1995.tb00037.x","article-title":"Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase","volume":"14","author":"B Haribabu","year":"1995","journal-title":"EMBO J"},{"issue":"5","key":"pcbi.1010263.ref035","doi-asserted-by":"crossref","first-page":"C1139","DOI":"10.1152\/ajpcell.00167.2010","article-title":"Pnck induces ligand-independent EGFR degradation by probable perturbation of the Hsp90 chaperone complex","volume":"300","author":"TB Deb","year":"2011","journal-title":"Am J Physiol Cell Physiol"},{"issue":"11","key":"pcbi.1010263.ref036","doi-asserted-by":"crossref","first-page":"101681","DOI":"10.1016\/j.isci.2020.101681","article-title":"Generating Multibillion Chemical Space of Readily Accessible Screening Compounds.","volume":"23","author":"OO Grygorenko","year":"2020","journal-title":"iScience."},{"issue":"13","key":"pcbi.1010263.ref037","doi-asserted-by":"crossref","first-page":"6784","DOI":"10.1021\/acs.jmedchem.9b01803","article-title":"Discovery of Highly Selective Inhibitors of Calmodulin-Dependent Kinases That Restore Insulin Sensitivity in the Diet-Induced Obesity in Vivo Mouse Model","volume":"63","author":"C Fromont","year":"2020","journal-title":"J Med Chem"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011672","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T00:00:00Z","timestamp":1700611200000}},{"DOI":"10.1371\/journal.pcbi.1010263","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:00:00Z","timestamp":1686182400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010263","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T13:53:14Z","timestamp":1686232394000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010263"}},"subtitle":[],"editor":[{"given":"Roland L.","family":"Dunbrack","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,5,26]]},"references-count":37,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5,26]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010263","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.06.01.494277","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,26]]}}}