{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:40:48Z","timestamp":1790646048988,"version":"4.1.0"},"reference-count":133,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser\/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. The methods utilised for CK2 can be applied to an array of protein kinases to aid in the discovery of chemical probes to further understand each kinase\u2019s biology, with wide-reaching implications for drug development.<\/jats:p>","DOI":"10.3390\/molecules26071977","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T21:37:03Z","timestamp":1617226623000},"page":"1977","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2498-2486","authenticated-orcid":false,"given":"Eleanor L.","family":"Atkinson","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9074-653X","authenticated-orcid":false,"given":"Jessica","family":"Iegre","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4045-0474","authenticated-orcid":false,"given":"Paul D.","family":"Brear","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Zhabina","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8683-4070","authenticated-orcid":false,"given":"Marko","family":"Hyv\u00f6nen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7355-2824","authenticated-orcid":false,"given":"David R.","family":"Spring","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1080\/14737140.2018.1527688","article-title":"A comprehensive review of protein kinase inhibitors for cancer therapy","volume":"18","author":"Kannaiyan","year":"2018","journal-title":"Expert Rev. 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