Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, California 94158, USA.
J Am Chem Soc. 2013 Apr 10;135(14):5298-301. doi: 10.1021/ja401221b. Epub 2013 Mar 29.
Fragment-based ligand design and covalent targeting of noncatalytic cysteines have been employed to develop potent and selective kinase inhibitors. Here, we combine these approaches, starting with a panel of low-molecular-weight, heteroaryl-susbstituted cyanoacrylamides, which we have previously shown to form reversible covalent bonds with cysteine thiols. Using this strategy, we identify electrophilic fragments with sufficient ligand efficiency and selectivity to serve as starting points for the first reported inhibitors of the MSK1 C-terminal kinase domain. Guided by X-ray co-crystal structures, indazole fragment 1 was elaborated to afford 12 (RMM-46), a reversible covalent inhibitor that exhibits high ligand efficiency and selectivity for MSK/RSK-family kinases. At nanomolar concentrations, 12 blocked activation of cellular MSK and RSK, as well as downstream phosphorylation of the critical transcription factor, CREB.
基于片段的配体设计和非催化半胱氨酸的共价靶向已被用于开发有效和选择性的激酶抑制剂。在这里，我们结合了这些方法，从一组低分子量、杂芳基取代的氰基丙烯酰胺开始，我们之前已经证明它们可以与半胱氨酸硫醇形成可逆的共价键。使用这种策略，我们确定了具有足够配体效率和选择性的亲电片段，可以作为第一个报道的 MSK1 C 端激酶结构域抑制剂的起始点。在 X 射线共晶结构的指导下，吲唑片段 1 被精心设计，得到了 12（RMM-46），这是一种可逆的共价抑制剂，对 MSK/RSK 家族激酶具有高的配体效率和选择性。在纳摩尔浓度下，12 阻断了细胞 MSK 和 RSK 的激活，以及关键转录因子 CREB 的下游磷酸化。
