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BAY-8400: A NovelnPotent and Selective DNA-PK Inhibitornwhich Shows Synergistic Efficacy in Combination with Targeted AlphanTherapies BAY-8400：一种新型的强效和选择性DNA-PK抑制剂，与靶向α疗法联合具有协同效应

Figshare Pub Date : 2021-08-24 DOI: 10.1021/acs.jmedchem.1c00762.s002

Markus Berger (216106), Lars Wortmann (6190562), Philipp Buchgraber (2063245), Ulrich Lücking (2614105), Sabine Zitzmann-Kolbe (340479), Antje M. Wengner (8769686), Benjamin Bader (2982786), Ulf Bömer (8283762), Hans Briem (1788724), Knut Eis (6190565), Hartmut Rehwinkel (4508851), Florian Bartels (8190036), Dieter Moosmayer (1399678), Uwe Eberspächer (8900651), Philip Lienau (2614111), Stefanie Hammer (222697), Christoph A. Schatz (11327011), Qiuwen Wang (1584481), Qi Wang (22418), Dominik Mumberg (167909), Carl F. Nising (2706721), Gerhard Siemeister (2614108)

{"title":"BAY-8400: A NovelnPotent and Selective DNA-PK Inhibitornwhich Shows Synergistic Efficacy in Combination with Targeted AlphanTherapies","authors":"Markus Berger (216106), Lars Wortmann (6190562), Philipp Buchgraber (2063245), Ulrich Lücking (2614105), Sabine Zitzmann-Kolbe (340479), Antje M. Wengner (8769686), Benjamin Bader (2982786), Ulf Bömer (8283762), Hans Briem (1788724), Knut Eis (6190565), Hartmut Rehwinkel (4508851), Florian Bartels (8190036), Dieter Moosmayer (1399678), Uwe Eberspächer (8900651), Philip Lienau (2614111), Stefanie Hammer (222697), Christoph A. Schatz (11327011), Qiuwen Wang (1584481), Qi Wang (22418), Dominik Mumberg (167909), Carl F. Nising (2706721), Gerhard Siemeister (2614108)","doi":"10.1021/acs.jmedchem.1c00762.s002","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.1c00762.s002","url":null,"abstract":"Eukaryotes have evolvedntwo major pathways to repair potentiallynlethal DNA double-strand breaks. Homologous recombination representsna precise, DNA-template-based mechanism available during the S andnG2 cell cycle phase, whereas non-homologous end joining, which requiresnDNA-dependent protein kinase (DNA-PK), allows for fast, cell cycle-independentnbut less accurate DNA repair. Here, we report the discovery of BAY-8400, a novel selective inhibitor of DNA-PK. Startingnfrom a triazoloquinoxaline, which had been identified as a hit fromna screen for ataxia telangiectasia and Rad3-related protein (ATR)ninhibitors with inhibitory activity against ATR, ATM, and DNA-PK,nlead optimization efforts focusing on potency and selectivity lednto the discovery of BAY-8400. In in vitro studies, BAY-8400 showed synergistic activity of DNA-PKninhibition with DNA damage-inducing targeted alpha therapy. Combinationnof PSMA-targeted thorium-227 conjugate BAY 2315497 treatment of humannprostate tumor-bearing mice with BAY-8400 oral treatmentnincreased antitumor efficacy, as compared to PSMA-targeted thorium-227nconjugate monotherapy.","PeriodicalId":523563,"journal":{"name":"Figshare","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147918192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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