{"id":13542,"date":"2024-01-18T08:38:34","date_gmt":"2024-01-18T08:38:34","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=13542"},"modified":"2024-01-24T08:38:44","modified_gmt":"2024-01-24T08:38:44","slug":"2024-discovery-and-optimization-of-dihydropteridone-derivatives-as-novel-plk1-and-brd4-dual-inhibitor-for-the-treatment-of-cancer","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2024-discovery-and-optimization-of-dihydropteridone-derivatives-as-novel-plk1-and-brd4-dual-inhibitor-for-the-treatment-of-cancer\/","title":{"rendered":"2024 &#8211; Discovery and optimization of dihydropteridone derivatives as novel PLK1 and BRD4 dual inhibitor for the treatment of cancer"},"content":{"rendered":"<p>In this study, we have designed, synthesized and tested three series of novel dihydropteridone derivatives possessing isoindolin-1-one or isoindoline moieties as potent inhibitors of PLK1\/BRD4. Remarkably, most of the compounds showed preferable inhibitory activity against PLK1 and BRD4. Compound SC10 exhibited excellent inhibitory activity with IC<sub>50<\/sub>\u00a0values of 0.3 nM and 60.8 nM against PLK1 and BRD4, respectively. Meanwhile, it demonstrated significant anti-proliferative activities against three tumor-derived cell lines (MDA-MB-231 IC<sub>50<\/sub>\u00a0= 17.3 nM, MDA-MB-361 IC<sub>50<\/sub>\u00a0= 8.4 nM, and MV4-11 IC<sub>50<\/sub>\u00a0= 5.4 nM). Moreover, SC10 exhibited moderate rat liver microsomal stability (CLint = 21.3 \u00b5L\u00b7min<sup>-1<\/sup>\u00b7mg<sup>-1<\/sup>), acceptable pharmacokinetic profile (AUC<sub>0-t<\/sub>\u00a0= 657 ng\u00b7h\u00b7mL<sup>-1<\/sup>, oral bioavailability of 21.4%) in Sprague-Dawley rats, reduced hERG toxicity, acceptable PPB and CYP450 inhibition. Further research indicated that SC10 could induce MV4-11 cell arrest at the S phase and apoptosis in a dose-dependent manner. This investigation provided us with an initial point for developing novel anticancer agents as dual inhibitors of PLK1 and BRD4.<\/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-13542","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\/ja\/wp-json\/wp\/v2\/resource_library\/13542","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=13542"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=13542"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=13542"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=13542"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=13542"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=13542"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=13542"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=13542"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=13542"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}