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Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-27 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01884 Fredrik Rahm 1 , Jenny Viklund 1 , Lionel Trésaugues 1 , Manuel Ellermann 2 , Anja Giese 2 , Ulrika Ericsson 1 , Rickard Forsblom 1 , Tobias Ginman 1 , Judith Günther 2 , Kenth Hallberg 1 , Johan Lindström 1 , Lars Boukharta Persson 1 , Camilla Silvander 1 , Antoine Talagas 1 , Laura Díaz-Sáez 3, 4 , Oleg Fedorov 3, 4 , Kilian V. M. Huber 3, 4 , Ioanna Panagakou 3, 4 , Paulina Siejka 3, 4 , Mátyás Gorjánácz 2 , Marcus Bauser 2 , Martin Andersson 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-27 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01884 Fredrik Rahm 1 , Jenny Viklund 1 , Lionel Trésaugues 1 , Manuel Ellermann 2 , Anja Giese 2 , Ulrika Ericsson 1 , Rickard Forsblom 1 , Tobias Ginman 1 , Judith Günther 2 , Kenth Hallberg 1 , Johan Lindström 1 , Lars Boukharta Persson 1 , Camilla Silvander 1 , Antoine Talagas 1 , Laura Díaz-Sáez 3, 4 , Oleg Fedorov 3, 4 , Kilian V. M. Huber 3, 4 , Ioanna Panagakou 3, 4 , Paulina Siejka 3, 4 , Mátyás Gorjánácz 2 , Marcus Bauser 2 , Martin Andersson 1
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Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo.(1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties.
中文翻译：
使用基于片段的筛选和基于结构的药物设计，创建一类新型的有效和选择性的MutT同源1（MTH1）抑制剂。
最近的文献都提出并质疑了MTH1作为一种新型的癌症靶标。BAY-707刚刚发布为目标验证小分子探针，用于评估药理学抑制MTH1在体外和体内对肿瘤细胞存活的影响。（1）在本报告中，我们描述了创建BAY-707的药物化学程序，其中基于片段的方法用于开发一系列高效且选择性的MTH1抑制剂。使用基于结构的药物设计和合理的药物化学方法，从片段起始点起效力提高了10,000倍以上，同时保持了高配体效率和类似药物的特性。
更新日期：2018-02-27
中文翻译：
使用基于片段的筛选和基于结构的药物设计，创建一类新型的有效和选择性的MutT同源1（MTH1）抑制剂。
最近的文献都提出并质疑了MTH1作为一种新型的癌症靶标。BAY-707刚刚发布为目标验证小分子探针，用于评估药理学抑制MTH1在体外和体内对肿瘤细胞存活的影响。（1）在本报告中，我们描述了创建BAY-707的药物化学程序，其中基于片段的方法用于开发一系列高效且选择性的MTH1抑制剂。使用基于结构的药物设计和合理的药物化学方法，从片段起始点起效力提高了10,000倍以上，同时保持了高配体效率和类似药物的特性。
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