{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:23:29Z","timestamp":1768523009251,"version":"3.49.0"},"posted":{"date-parts":[[2025,7,12]]},"group-title":"Microbiology","reference-count":27,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,12]],"date-time":"2025-07-12T00:00:00Z","timestamp":1752278400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Stuctural Genomics Consortium","award":["1097737"],"award-info":[{"award-number":["1097737"]}]},{"DOI":"10.13039\/501100000092","name":"Ontario Genomics Institute","doi-asserted-by":"crossref","award":["OGI-196"],"award-info":[{"award-number":["OGI-196"]}],"id":[{"id":"10.13039\/501100000092","id-type":"DOI","asserted-by":"crossref"}]},{"name":"EUbOPEN","award":["875510"],"award-info":[{"award-number":["875510"]}]},{"name":"National Institute of Health","award":["R01AI162789-01"],"award-info":[{"award-number":["R01AI162789-01"]}]},{"name":"National Institute of Health","award":["R01GM138520-04"],"award-info":[{"award-number":["R01GM138520-04"]}]},{"name":"National Institute of Health","award":["P30CA016086-34"],"award-info":[{"award-number":["P30CA016086-34"]}]},{"name":"National Institute of Health","award":["S10OD032476"],"award-info":[{"award-number":["S10OD032476"]}]},{"name":"NC Biotech Center Institutional Support","award":["2018-IDG-1030"],"award-info":[{"award-number":["2018-IDG-1030"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Candida albicans is a growing global health threat, causing 1.5 million invasive infections and 1 million deaths annually. Yeast casein kinase 2 (Yck2) in\n                  <jats:italic>C. albicans<\/jats:italic>\n                  has emerged as an antifungal target of the kinase inhibitor LY364947 (\n                  <jats:bold>LY<\/jats:bold>\n                  ). Herein, we report Yck2 structure-activity relationships for 3,4- and 3,4,5-substituted pyrazole analogs of\n                  <jats:bold>LY<\/jats:bold>\n                  . X-ray crystallography and in vitro profiling revealed the importance of the hinge-binding heterocycle for Yck2 inhibition and fungal kinome selectivity. A hydrogen-bond network between the inhibitor, a bound water molecule, and catalytic residues within the ATP pocket was identified as a key determinant of selectivity over other fungal and human kinases. Phenol analog\n                  <jats:bold>11<\/jats:bold>\n                  showed remarkable selectivity for Yck2 and Yck22 over all other\n                  <jats:italic>C. albicans<\/jats:italic>\n                  protein kinases. Several of the\n                  <jats:bold>LY<\/jats:bold>\n                  analogs, including\n                  <jats:bold>11<\/jats:bold>\n                  , demonstrated improved antifungal activity. These findings provide a framework for translating human kinase inhibitors into highly selective antifungal Yck2 inhibitors.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"664496v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.12.664496","type":"posted-content","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T04:20:11Z","timestamp":1752380411000},"source":"Crossref","is-referenced-by-count":0,"title":["Structure-activity Relationship for Diarylpyrazoles as Inhibitors of the Fungal Kinase Yck2"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-2475-7366","authenticated-orcid":false,"given":"David J.","family":"Shirley","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9106-9974","authenticated-orcid":false,"given":"Bonnie","family":"Yiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7877-8562","authenticated-orcid":false,"given":"Ikeer","family":"Mancera-Ortiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8663-1425","authenticated-orcid":false,"given":"Peter J.","family":"Stogios","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4198-8214","authenticated-orcid":false,"given":"Zhongle","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2821-9269","authenticated-orcid":false,"given":"Nicole","family":"Robbins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6445-5766","authenticated-orcid":false,"given":"Luke","family":"Whitesell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5797-0110","authenticated-orcid":false,"given":"Leah E.","family":"Cowen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5973-5798","authenticated-orcid":false,"given":"David H.","family":"Drewry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4181-8223","authenticated-orcid":false,"given":"Timothy M.","family":"Willson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025071513351702000_2025.07.12.664496v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.103953"},{"key":"2025071513351702000_2025.07.12.664496v1.2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.REV120.013731"},{"key":"2025071513351702000_2025.07.12.664496v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2019.12.008"},{"key":"2025071513351702000_2025.07.12.664496v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-57346-z"},{"key":"2025071513351702000_2025.07.12.664496v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.09.040"},{"key":"2025071513351702000_2025.07.12.664496v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3374"},{"key":"2025071513351702000_2025.07.12.664496v1.7","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c00097"},{"key":"2025071513351702000_2025.07.12.664496v1.8","doi-asserted-by":"publisher","DOI":"10.3390\/jof6040230"},{"key":"2025071513351702000_2025.07.12.664496v1.9","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02183-23"},{"key":"2025071513351702000_2025.07.12.664496v1.10","unstructured":"Truong, C. 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