Multiprotein Dynamic Combinatorial Chemistry: A Strategy for the Simultaneous Discovery of Subfamily-Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3
Multiprotein Dynamic Combinatorial Chemistry: A Strategy for the Simultaneous Discovery of Subfamily-Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3
复制标题
DOI：
10.1002/asia.201800729
复制
发表时间：
2018-10-04
影响因子：
4.1
通讯作者：
Woon, Esther C. Y.
中科院分区：
文献类型：
--
作者：
Das, Mohua;Yang, Tianming;Woon, Esther C. Y.
动态组合化学（DCC）是一种用于发现生物分子配体的强大超分子方法。迄今为止，大多数（如果不是全部）生物模板化 DCC 系统仅采用单个生物分子来指导自组装过程。为了扩大 DCC 的范围，本文开发了一种新颖的多蛋白 DCC 策略，该策略将两性离子“热标签”的辨别能力与差示扫描荧光测定法的灵敏度相结合。该策略高度敏感，可以区分配体与结构相似的亚家族成员的结合。通过这种策略，可以同时鉴定针对两种临床上重要的表观遗传酶的亚家族选择性探针：FTO（7；IC50 = 2.6μm）和ALKBH3（8；IC50 = 3.7μm）。迄今为止，这是亚家族选择性 ALKBH3 抑制剂的第一份报告。原则上，所开发的策略可以适用于广泛的蛋白质；因此它具有广泛的科学意义。
Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically templated DCC systems employ only a single biomolecule to direct the self-assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic "thermal tag" with the sensitivity of differential scanning fluorimetry. This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily-selective probes against two clinically important epigenetic enzymes: FTO (7; IC50 = 2.6 mu m) and ALKBH3 (8; IC50 = 3.7 mu m). To date, this is the first report of a subfamily-selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest.