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 μm) and ALKBH3 (8; IC₅₀=3.7 μm). 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.

中文翻译：

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多蛋白动态组合化学：同时发现核酸脱甲基酶FTO和ALKBH3的亚家族选择性抑制剂的策略。

动态组合化学（DCC）是一种强大的超分子方法，可用于发现生物分子的配体。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，有可能同时针对两种临床上重要的表观遗传酶识别亚科选择性探针：FTO（7 ; IC ₅₀ = 2.6μ米）和ALKBH3（8 ; IC ₅₀ = 3.7μ米）。迄今为止，这是亚家族选择性ALKBH3抑制剂的首次报道。原则上，已开发的策略可以适应多种蛋白质；因此，它具有广泛的科学意义。