Dept. of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot 7610001, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel-Aviv 6997801, Israel.
J Am Chem Soc. 2023 Feb 15;145(6):3346-3360. doi: 10.1021/jacs.2c08853. Epub 2023 Feb 4.
Electrophiles for covalent inhibitors that are suitable for in vivo administration are rare. While acrylamides are prevalent in FDA-approved covalent drugs, chloroacetamides are considered too reactive for such purposes. We report sulfamate-based electrophiles that maintain chloroacetamide-like geometry with tunable reactivity. In the context of the BTK inhibitor ibrutinib, sulfamate analogues showed low reactivity with comparable potency in protein labeling, in vitro, and cellular kinase activity assays and were effective in a mouse model of CLL. In a second example, we converted a chloroacetamide Pin1 inhibitor to a potent and selective sulfamate acetamide with improved buffer stability. Finally, we show that sulfamate acetamides can be used for covalent ligand-directed release (CoLDR) chemistry, both for the generation of "turn-on" probes as well as for traceless ligand-directed site-specific labeling of proteins. Taken together, this chemistry represents a promising addition to the list of electrophiles suitable for in vivo covalent targeting.
用于可体内给药的共价抑制剂的亲电试剂很少。虽然丙烯酰胺在 FDA 批准的共价药物中很常见，但氯乙酰胺由于反应性过高而不适合此类用途。我们报告了基于磺胺的亲电试剂，它们具有可调节反应性的类似氯乙酰胺的几何形状。在 BTK 抑制剂伊布替尼的背景下，磺胺类似物在蛋白质标记、体外和细胞激酶活性测定中的反应性较低，但具有相当的效力，并且在 CLL 的小鼠模型中有效。在第二个例子中，我们将氯乙酰胺 Pin1 抑制剂转化为具有更好缓冲稳定性的强效和选择性磺胺乙酰胺。最后，我们表明磺胺乙酰胺可用于共价配体定向释放 (CoLDR) 化学，既可以生成“开启”探针，也可以用于无痕迹配体定向的蛋白质特异性标记。总之，这种化学为适合体内共价靶向的亲电试剂列表增添了一种有前途的方法。
