{"id":13385,"date":"2023-05-05T10:11:38","date_gmt":"2023-05-05T10:11:38","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13385"},"modified":"2024-01-12T13:50:00","modified_gmt":"2024-01-12T13:50:00","slug":"2023-design-synthesis-and-biological-evaluation-of-novel-dihydropteridone-derivatives-possessing-oxadiazoles-moiety-as-potent-inhibitors-of-plk1","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2023-design-synthesis-and-biological-evaluation-of-novel-dihydropteridone-derivatives-possessing-oxadiazoles-moiety-as-potent-inhibitors-of-plk1\/","title":{"rendered":"2023 &#8211; Design, synthesis, and biological evaluation of novel dihydropteridone derivatives possessing oxadiazoles moiety as potent inhibitors of PLK1"},"content":{"rendered":"<p>Polo like kinase\u00a01 (PLK1) is a serine\/threonine kinase that is widely distributed in eukaryotic cells and plays an important role in multiple phases of the cell cycle. Its importance in tumorigenesis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of novel dihydropteridone derivatives (<strong>13a-13v<\/strong>\u00a0and\u00a0<strong>21g-21l<\/strong>) possessing\u00a0oxadiazoles\u00a0moiety as potent inhibitors of PLK1. Compound\u00a0<strong>21g<\/strong>\u00a0exhibited improved PLK1 inhibitory capability with an IC<sub>50<\/sub>\u00a0value of 0.45\u00a0nM and significant anti-proliferative activities against four tumor-derived cell lines (MCF-7 IC<sub>50<\/sub>\u00a0=\u00a08.64\u00a0nM, HCT-116 IC<sub>50<\/sub>\u00a0=\u00a026.0\u00a0nM, MDA-MB-231 IC<sub>50<\/sub>\u00a0=\u00a014.8\u00a0nM and MV4-11 IC<sub>50<\/sub>\u00a0=\u00a047.4\u00a0nM) with better\u00a0pharmacokinetic\u00a0characteristics than\u00a0BI2536\u00a0in mice (AUC<sub>0-t<\/sub>\u00a0=\u00a011\u00a0227\u00a0ng\u00a0h\u00a0mL<sup>\u22121<\/sup>\u00a0<em>vs<\/em>\u00a0556\u00a0ng\u00a0h\u00a0mL<sup>\u22121<\/sup>). Moreover,\u00a0<strong>21g<\/strong>\u00a0exhibited moderate liver microsomal stability and excellent\u00a0pharmacokinetic\u00a0profile (AUC<sub>0-t<\/sub>\u00a0=\u00a011227\u00a0ng\u00a0h\u00a0mL<sup>\u22121<\/sup>, oral bioavailability of 77.4%) in Balb\/c mice, acceptable\u00a0PPB, improved PLK1 inhibitory selectivity, and no apparent toxicity was observed in the\u00a0acute toxicity\u00a0assay (20\u00a0mg\/kg). Further investigation showed that\u00a0<strong>21\u00a0g<\/strong>\u00a0could arrest HCT-116\u00a0cells in\u00a0G2 phase\u00a0and induce apoptosis in a dose-dependent manner. These results indicate that\u00a0<strong>21g<\/strong>\u00a0is a promising PLK1 inhibitor.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,76],"therapeutic_areas":[54,57],"target_categories":[61],"target_families":[333],"targets":[92],"resource_keyword":[],"class_list":["post-13385","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-drug-discovery","therapeutic_areas-cardiac-safety-cipa","therapeutic_areas-cancer","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv11-1-herg"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/13385","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=13385"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=13385"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=13385"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=13385"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=13385"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=13385"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=13385"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=13385"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=13385"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}