Sprint Bioscience AB, Novum , 14157 Huddinge , Sweden.
Bayer AG , Muellerstrasse 178 , 13353 Berlin , Germany.
J Med Chem. 2018 Mar 22;61(6):2533-2551. doi: 10.1021/acs.jmedchem.7b01884. Epub 2018 Mar 7.
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.
近期文献提出并质疑了 MTH1 作为一个新的癌症靶点。BAY-707 刚刚被发表为一种用于评估 MTH1 药理学抑制对肿瘤细胞存活的影响的小分子探针，无论是在体外还是体内。（1）在本报告中，我们描述了创建 BAY-707 的药物化学计划，其中使用基于片段的方法来开发一系列具有高活性和选择性的 MTH1 抑制剂。通过基于结构的药物设计和合理的药物化学方法，从起始片段开始，将活性提高了 10000 多倍，同时保持了高配体效率和类药性。
