{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:30:03Z","timestamp":1791318603635,"version":"4.3.1"},"reference-count":59,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,27]],"date-time":"2022-11-27T00:00:00Z","timestamp":1669507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bayer AG","award":["INST 161\/920-1 FUGG"],"award-info":[{"award-number":["INST 161\/920-1 FUGG"]}]},{"name":"Boehringer Ingelheim","award":["INST 161\/920-1 FUGG"],"award-info":[{"award-number":["INST 161\/920-1 FUGG"]}]},{"name":"Canada Foundation for Innovation","award":["INST 161\/920-1 FUGG"],"award-info":[{"award-number":["INST 161\/920-1 FUGG"]}]},{"name":"Eshelman Institute for Innovation, Genentech, Genome Canada","award":["INST 161\/920-1 FUGG"],"award-info":[{"award-number":["INST 161\/920-1 FUGG"]}]},{"name":"FUGG","award":["INST 161\/920-1 FUGG"],"award-info":[{"award-number":["INST 161\/920-1 FUGG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The PCTAIRE subfamily belongs to the CDK (cyclin-dependent kinase) family and represents an understudied class of kinases of the dark kinome. They exhibit a highly conserved binding pocket and are activated by cyclin Y binding. CDK16 is targeted to the plasma membrane after binding to N-myristoylated cyclin Y and is highly expressed in post-mitotic tissues, such as the brain and testis. Dysregulation is associated with several diseases, including breast, prostate, and cervical cancer. Here, we used the N-(1H-pyrazol-3-yl)pyrimidin-4-amine moiety from the promiscuous inhibitor 1 to target CDK16, by varying different residues. Further optimization steps led to 43d, which exhibited high cellular potency for CDK16 (EC50 = 33 nM) and the other members of the PCTAIRE and PFTAIRE family with 20\u2013120 nM and 50\u2013180 nM, respectively. A DSF screen against a representative panel of approximately 100 kinases exhibited a selective inhibition over the other kinases. In a viability assessment, 43d decreased the cell count in a dose-dependent manner. A FUCCI cell cycle assay revealed a G2\/M phase cell cycle arrest at all tested concentrations for 43d, caused by inhibition of CDK16.<\/jats:p>","DOI":"10.3390\/ijms232314834","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T04:56:25Z","timestamp":1669611385000},"page":"14834","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Discovery of 3-Amino-1H-pyrazole-Based Kinase Inhibitors to Illuminate the Understudied PCTAIRE Family"],"prefix":"10.3390","volume":"23","author":[{"given":"Jennifer Alisa","family":"Amrhein","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"},{"name":"Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7835-8067","authenticated-orcid":false,"given":"Lena Marie","family":"Berger","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"},{"name":"Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0423-6593","authenticated-orcid":false,"given":"Amelie","family":"Tjaden","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"},{"name":"Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3294-2660","authenticated-orcid":false,"given":"Andreas","family":"Kr\u00e4mer","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"},{"name":"Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lewis","family":"Elson","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"},{"name":"Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3581-208X","authenticated-orcid":false,"given":"Tuomas","family":"Tolvanen","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institute, Solnav\u00e4gen 1, 17177 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Martinez-Molina","sequence":"additional","affiliation":[{"name":"Pelago Bioscience AB, Scheeles V\u00e4g 1, 17165 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Kaiser","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Schubert-Zsilavecz","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2402-4157","authenticated-orcid":false,"given":"Susanne","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"},{"name":"Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5995-6494","authenticated-orcid":false,"given":"Stefan","family":"Knapp","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"},{"name":"Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), DKTK Site Frankfurt-Mainz, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-9468","authenticated-orcid":false,"given":"Thomas","family":"Hanke","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt am Main, Germany"},{"name":"Structural Genomics Consortium, Buchmann Institute for Life Sciences, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1038\/s41467-020-16559-0","article-title":"Quantifying CDK Inhibitor Selectivity in Live Cells","volume":"11","author":"Wells","year":"2020","journal-title":"Nat. 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